CN107108653B - Pyrazolo thiazolium compounds and medicine - Google Patents

Pyrazolo thiazolium compounds and medicine Download PDF

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CN107108653B
CN107108653B CN201580058944.7A CN201580058944A CN107108653B CN 107108653 B CN107108653 B CN 107108653B CN 201580058944 A CN201580058944 A CN 201580058944A CN 107108653 B CN107108653 B CN 107108653B
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pyrazolo
thiazole
pyrimidine
piperidin
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CN107108653A (en
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柴佳伸
秋山聪志
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Nippon Shinyaku Co Ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/25—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids with polyoxyalkylated alcohols, e.g. esters of polyethylene glycol
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Abstract

The purpose of the present invention is to provide a kind of compounds with excellent JAK1 inhibiting effect.As the present invention, the pyrazolo thiazolium compounds or its pharmaceutically acceptable salt for example indicated with the following general formula [1] can be enumerated.

Description

Pyrazolo thiazolium compounds and medicine
Technical field
The present invention relates to contain novel pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate Medical composition as effective component.
Background technique
Tyrosine kinase is the signal transduction system in the cell by the enzyme of the tyrosine residue of protein specifically phosphorylation It plays an important role in system, participates in the extensive biology function such as existence, differentiation, proliferation, secretion of cell.As with cell The relevant intracellular tyrosine kinase of factor signal transduction, it is known that Janus kinases (Janus Kinase, also referred to as JAK) family Race.There are JAK1, JAK2, JAK3,4 kinds of tyrosine kinase 2 (Tyrosine Kinase 2, also referred to as Tyk2) in JAK family Enzyme.Through cell factor in conjunction with cytokine receptor, JAK is phosphorylated, by the tyrosine residue phosphorylation of receptor.Then, Intracellular existing signal transduction and activating transcription factor (signal transducer and activator of Transcription, also referred to as STAT) it associates with the tyrosine residue of receptor being phosphorylated, the tyrosine residue of STAT is logical JAK is crossed to be phosphorylated.Think that the STAT being phosphorylated forms dimer, be transferred in core, induces target base as transcription factor The transcription activating of cause causes the activation of cell.JAK/STAT system is the most important of the cell factor in immunocompetent cell Cellular Signaling Transduction Mediated system (non-patent literature 1), by the combination of 4 kinds of JAK and 7 kinds of STAT, can be carried out about 40 kinds of cells because The signal transduction of son, result, it is believed that the exception for exception and the cytokine signaling conduction that cell factor generates not only is exempted from itself The various immunological diseases such as epidemic disease disease, allergy are related with inflammation disease, and the disease with cancer etc. with a variety of different pathologicals There is very big association.These inhibit the chemical substance of JAK/STAT system activation to be closed as the new medicine of these diseases Note, in fact, JAK inhibitor as myelofibrosis, polycythemia vera and rheumatoid arthritis medicine Through being recognized in the U.S. and Japan etc..In addition, being also contemplated that other autoimmune diseases (such as psoriatic arthritis, childhood Type arthritis, the graceful disease in Karst, systemic lupus erythematosus, xerodermosteosis, multiple sclerosis, inflammatory bowel disease, Bei Qie Special disease, myasthenia gravis, type-1 diabetes mellitus, immunoglobulin nephrosis, autoimmune thyroid disease, psoriasis, chorionitis, wolf Sore ephritis, xerophthalmia, vasculitis are (such as aorto-arteritis, giant cell arteritis, microscopic polyangitis, granulomatous more Vasculitis, eosinophilic granuloma's property Polyangiitis), dermatomyositis, polymyositis, neuromyelitis optica), diseases associated with inflammation (such as It is atopic dermatitis, contact dermatitis, eczema, pruritus, food hypersenstivity, bronchial asthma, Eosinophilic's pneumonia, chronic Obstructive lung disease, allergic rhinitis, chronic nasosinusitis, Eosinophilic's nasosinusitis, nasal polyp, allergic conjunctivitis, bone Arthritis, ankylosing spondylitis, Kawasaki disease, Buerger's disease, nodular polyarteritis, IgA vasculitis), proliferative diseases (such as Solid carcinoma, blood cancer, lymphoid malignancies, bone marrow proliferative diseases, Huppert's disease, pulmonary fibrosis, acidophil granules Cytosis), sudden deafness, diabetic nephropathy, alopecia areata, bone marrow transplant rejection or organ transplantation rejection etc. therapeutic effect, Now, some diseases in above-mentioned disease in Japan and also implement clinical test in US and European first.
Various biological studies show that JAK1 therein has important work relevant to the signal transduction of cytokine profiles With (referring to non-patent literature 2,3,4), this means that JAK1 inhibitor for such as autoimmune disease: psoriatic arthritis (referring for example to non-patent literature 5), juvenile arthritis (referring for example to non-patent literature 6), the graceful disease in Karst are (referring for example to non- Patent document 6), systemic lupus erythematosus (referring for example to non-patent literature 7), xerodermosteosis is (referring for example to non-patent Document 8), multiple sclerosis (referring for example to non-patent literature 9), inflammatory bowel disease (referring for example to non-patent literature 10), Bei Qie Special disease (referring for example to non-patent literature 11), myasthenia gravis (referring for example to non-patent literature 12), type-1 diabetes mellitus (such as are joined According to non-patent literature 9), immunoglobulin nephrosis (referring for example to non-patent literature 13), autoimmune thyroid disease (such as join According to non-patent literature 14), psoriasis (referring for example to non-patent literature 15), chorionitis (referring for example to non-patent literature 16), wolf Sore ephritis (referring for example to non-patent literature 17), xerophthalmia (referring for example to non-patent literature 18), vasculitis are (referring for example to non- Patent document 19,20,21,22,23), dermatomyositis (referring for example to non-patent literature 24), polymyositis be (referring for example to non-patent Document 24), neuromyelitis optica (referring for example to non-patent literature 25), diseases associated with inflammation: atopic dermatitis (referring for example to it is non-specially Sharp document 26), contact dermatitis (referring for example to non-patent literature 27), eczema (referring for example to non-patent literature 28), pruritus (referring for example to non-patent literature 29), food hypersenstivity (referring for example to non-patent literature 30), bronchial asthma are (referring for example to non-special Sharp document 31), Eosinophilic's pneumonia (referring for example to non-patent literature 32), chronic obstructive pulmonary disease is (referring for example to non- Patent document 33), allergic rhinitis (referring for example to non-patent literature 31), chronic nasosinusitis is (referring for example to non-patent literature 34), Eosinophilic's nasosinusitis, nasal polyp (referring for example to non-patent literature 35), allergic conjunctivitis are (referring for example to non- Patent document 36), osteoarthritis (referring for example to non-patent literature 37), ankylosing spondylitis (referring for example to non-patent literature 6), Kawasaki disease (referring for example to non-patent literature 38), Buerger's disease (referring for example to non-patent literature 39), nodular polyarteritis (example Such as referring to non-patent literature 40), IgA vasculitis (referring for example to non-patent literature 41), proliferative diseases: solid carcinoma, blood Cancer, lymphoid malignancies, bone marrow proliferative diseases, Huppert's disease (referring for example to non-patent literature 42,43,44), Sudden deafness (referring for example to non-patent literature 45), diabetic nephropathy (referring for example to non-patent literature 46), alopecia areata (referring for example to Non-patent literature 47), the treatment of the diseases such as bone marrow transplant rejection or organ transplantation rejection it is useful, such as implement clinic below Test.Rheumatoid arthritis (https: //clinicaltrials.gov/NCT01888874, NCT02049138), clone Family name disease (https: //clinicaltrials.gov/NCT02365649), non-small cell lung cancer (https: // Clinicaltrials.gov/NCT02257619), cancer of pancreas (https: //clinicaltrials.gov/ NCT01858883), myelofibrosis (https: //clinicaltrials.gov/NCT01633372), psoriasis (https://clinicaltrials.gov/NCT02201524)。
In addition, cell factor inhibitors below have listed in the relevant cytokine signaling conduction of JAK1.
(1) IL-6 (also referred to as interleukin-6): rheumatoid arthritis, the graceful disease of juvenile arthritis and Karst are controlled Treat medicine (referring to non-patent literature 48,49,50).
(2) IL-2: the medicine of the acute rejection after kidney transplant (referring to non-patent literature 51).
Also implementing following cell factor inhibitors clinical test now.
(3) IL-4 and IL-13: bronchial asthma, atopic dermatitis, Eosinophilic's nasosinusitis, nasal polyp and thermophilic Eosinophil esophagitis medicine (referring to non-patent literature 31).
(4) IL-13: pulmonary fibrosis medicine (https: //clinicaltrials.gov/NCT02036580).
(5) IL-5: bronchial asthma, chronic obstructive pulmonary disease, eosinophilia, eosinophilic granuloma's property are more Vasculitis, Eosinophilic's esophagitis, Eosinophilic's nasosinusitis, nasal polyp and treatment of atopic dermatitis medicine (ginseng According to non-patent literature 31, non-patent literature 52).
(6) IFN α (also referred to as interferon-' alpha '): systemic lupus erythematosus medicine (referring to non-patent literature 7).
(7) IL-31: treatment of atopic dermatitis medicine (https: //clinicaltrials.gov/NCT01986933).
(8) TSLP (Thymic stromal lymphopoietin: also referred to as thymic stromal lymphopoietin): branch San bronchial asthma (https: //clinicaltrials.gov/NCT02054130), treatment of atopic dermatitis medicine (https: // clinicaltrials.gov/NCT00757042)。
Therefore, the inhibition of JAK1 signal transduction is prevention or treatment autoimmune disease, diseases associated with inflammation and proliferative Disease etc. by the extremely caused disease of JAK1 signal transduction ideal style.
As the compound with JAK inhibitory, it was recently reported that [1,2,4] triazol [1,5-a] pyridine compounds (such as Referring to patent document 1,2), 3 ring pyrazino ketone compound objects (referring for example to patent document 3), Pyrrolopyrimidine compounds (such as join According to patent document 4~7), phthalazine compound (referring for example to patent document 8), imidazo pyrrolopyridine compounds (referring for example to Patent document 9, non-patent literature 53), diaminostilbene, 2,4- triazole compounds (referring for example to non-patent literature 54), pyrazolo [1,5-a] pyridine (referring for example to patent document 10), imidazo [1,2-a] pyridine (referring for example to patent document 11,12), benzo Imidazolium compounds (referring for example to patent document 13), 7- azaindole compounds (referring for example to patent document 14) etc., but wherein Pyrazolo [5,1-b] [1,3] thiazolium compounds as the compounds of this invention is not disclosed.
Existing technical literature
Non-patent literature
Non-patent literature 1:O ' Shea etc., Immunity, 2012,36,542-550.
Non-patent literature 2:O ' Sullivan etc., Mol.Immunol., 2007,44,2497-2506.
Non-patent literature 3:Quint á s-Cardama etc., Nat.Rev.Drug Discov., 2011,10,127-140.
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Non-patent literature 8:Gliozzi etc., J.Autoimmun., 2013,40,122-133.
Non-patent literature 9:Neurath etc., Cytokine Growth Factor Rev., 2011,22,83-89.
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Non-patent literature 11:Akdeniz etc., Ann.Acad.Med.Singapore, 2004,33,596-599.
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Non-patent literature 13:Goto etc., Clin.Immunol., 2008,126,260-269.
Non-patent literature 14:Nanba etc., Thyroid, 2009,19,495-501.
Non-patent literature 15:Strober etc., Br.J.Dermatol., 2013,169,992-999.
Non-patent literature 16:Christner etc., Curr.Opin.Rheumatol., 2004,16,746-752.
Non-patent literature 17:Dong etc., Lupus, 2007,16,101-109.
Non-patent literature 18:Lim etc., Cornea, 2015,34,248-252.
Non-patent literature 19:Saadoun etc., Arthritis Rheumatol., 2015,67,1353-1360.
Non-patent literature 20:Kieffer etc., Rev.Med.Interne., 2014,35,56-59.
Non-patent literature 21:Takenaka etc., Clin.Rheumatol., 2014,33,287-289.
Non-patent literature 22:Kobold etc., Clin.Exp.Rheumatol., 1999,17,433-440.
Non-patent literature 23:Vaglio etc., Allergy, 2013,68,261-273.
Non-patent literature 24:Gono etc., Rheumatology, 2014,53,2196-2203.
Non-patent literature 25:Araki etc., Neurology, 2014,82,1302-1306.
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Patent document
Patent document 1:WO2010/149769
Patent document 2:WO2010/010190
Patent document 3:WO2012/085176
Patent document 4:WO2009/114512
Patent document 5:WO2011/075334
Patent document 6:WO2012/022045
Patent document 7:WO2012/054364
Patent document 8:WO2012/037132
Patent document 9:WO2011/086053
Patent document 10:WO2011/101161
Patent document 11:WO2011/076419
Patent document 12:JP2011/136925
Patent document 13:WO2005/066156
Patent document 14:WO2007/084557
Summary of the invention
The technical problems to be solved by the invention
The purpose of the present invention is to provide a kind of compounds with excellent JAK1 inhibiting effect.
Technical scheme applied to solve the technical problem
The present inventor has found after conscientiously studying, the pyrazolo thiazolium compounds indicated with the following general formula (I) or its pharmacy Upper acceptable salt or its solvate (the compounds of this invention is otherwise referred to as in specification) inhibit to make with excellent JAK1 With so as to complete the present invention.
That is, the present invention can enumerate the invention of following (I)~(XVII).
(I) the pyrazolo thiazolium compounds or its pharmaceutically acceptable salt that are indicated with the following general formula [1] or its solvent close Object.
[changing 1]
In formula,
R1Indicate hydrogen, alkyl or alkoxy,
Z expression-OR3Or-NR4R5,
The R3Indicate alkyl, the alkyl being substituted by cycloalkyl, naphthenic base, aryl or heteroaryl,
The R4Indicate hydrogen or alkyl,
The R5Indicate alkyl, naphthenic base or saturated heterocyclyl,
R5Described in alkyl, naphthenic base can be selected from the group 1 of (1)~(6) or 2 groups replace:
(1) hydroxyl,
(2) alkoxy and difluoro alkoxy,
(3) naphthenic base, the alkyl-substituted naphthenic base of quilt (difluoro alkoxy) and the naphthenic base replaced by alkoxyalkyl,
(4) can by (difluoro alkoxy) alkyl-substituted saturated heterocyclyl,
(5) aryl, the aryl being optionally substituted by halogen and the aryl replaced by alkoxy and
(6) itrile group,
R5Described in saturated heterocyclyl can be selected from the group any 1 groups of (1)~(3) and replaced:
(1) alkyl,
(2) alkyl-carbonyl and
(3) alkoxy carbonyl,
R2Indicate hydroxyl or-NHR8,
The R8Indicate heteroaryl, be optionally substituted by halogen heteroaryl, by alkyl-substituted heteroaryl ,-COL1、-COOL2Or- SO2L3,
The L1It is any 1 group for being selected from the group (1)~(5):
(1) alkyl, a halogenated alkyl, dihalo alkyl, tri haloalkyl and the alkyl replaced by alkoxy,
(2) naphthenic base,
(3) aryl,
(4) heteroaryl and
(5) dialkyl amido and cycloalkyl amino,
The L2It is any 1 group for being selected from the group (1)~(3):
(1) alkyl, a halogenated alkyl, dihalo alkyl, tri haloalkyl and the alkyl replaced by alkoxy,
(2) naphthenic base and
(3) dialkyl aminoalkyl,
The L3Indicate alkyl or cycloalkyl.
(II)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (I), wherein R1 It is hydrogen.
(III)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (II), wherein
Z is-NR4R5,
The R4It is hydrogen,
The R5It is alkyl or cycloalkyl,
R5Described in alkyl, naphthenic base can be selected from the group 1 group of (1)~(3) and be replaced:
(1) hydroxyl,
(2) alkoxy and
(3) naphthenic base,
R2It is hydroxyl or-NHR8,
The R8Be heteroaryl, the heteroaryl that is optionally substituted by halogen, by alkyl-substituted heteroaryl ,-COL1Or-COOL2,
The L1It is any 1 group for being selected from the group (1)~(4):
(1) alkyl, a halogenated alkyl, dihalo alkyl, tri haloalkyl and the alkyl replaced by alkoxy,
(2) naphthenic base,
(3) aryl and
(4) heteroaryl,
The L2It is alkyl, a halogenated alkyl, dihalo alkyl, tri haloalkyl, the alkyl or ring replaced by alkoxy Alkyl.
(IV)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (III), wherein
R5Be alkyl, the alkyl that is optionally substituted by a hydroxyl group, by alkyl that cyclopropyl replaces or the alkyl replaced by alkoxy,
R2It is-NHR8。
(V)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (III), wherein
R5It is the alkyl or the alkyl replaced by cyclopropyl that carbon number is 2~6,
R2It is-NHR8,
R8It is-COL1Or-COOL2,
The L1It is the alkyl or cyclopropyl that carbon number is 2~6,
The L2It is alkyl or cyclopropyl.
(VI)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (I), wherein pyrrole Simultaneously thiazolium compounds is compound described in any one of following (1)~(135) to azoles:
(1) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(2) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(3) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(4) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(5) N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(6) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(7) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(8) N- [1- ({ 6- [({ 1- [(difluoro-methoxy) methyl] cyclopropyl } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(9) N- [1- ({ 6- [({ 1- [(difluoro-methoxy) methyl] cyclobutyl } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(10) N- [1- ({ 6- [({ 1- [(difluoro-methoxy) methyl] cyclopenta } methyl) amino] -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(11) N- [1- ({ 6- [({ 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrans -4- base } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(12) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(13) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(14) N- (1- [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(15) [({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(16) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(17) N- (1- [6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(18) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) two Fluorakil 100 of -2,2-,
(19) N- (1- { [6- { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(20) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] (4- hydroxy piperidine -1- base) ketone,
(21) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) the fluoro- 2- methylpropane -2- base ester of carbamic acid 1-,
(22) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(23) [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) ketone,
(24) (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(25) (1- { [6- { [(2S) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(26) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(27) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes,
(28) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(29) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide,
(30) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) pyridine -3- carboxylic acid amides,
(31) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) thiophene -2- carboxylic acid amides,
(32) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(33) 1- cyclopropyl -3- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urea,
(34) [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] [4- (pyrimidine -2 --amino) piperidin-1-yl] ketone,
(35) N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(36) [({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(37) N- [1- ({ 6- [(1- methoxyl group -2- methylpropane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(38) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(39) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes,
(40) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(41) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide,
(42) N- (1- { [6- (cyclo propyl methoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(43) N- [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(44) N- (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(45) N- (1- { [6- (cyclopentyloxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(46) N- (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(47) N- [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(48) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] [4- (1,2-Azoles -3- base amino) piperidin-1-yl] ketone,
(49) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone,
(50) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] { 4- [(3- methyl-1,2-Azoles -5- base) amino] piperidin-1-yl } ketone,
(51) N- (1- { [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(52) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- hydroxyl Piperidin-1-yl) ketone,
(53) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) methyl carbamate,
(54) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid propane -2- base ester,
(55) [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(56) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) ketone,
(57) (1- { [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(58) [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(59) (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) methyl carbamate,
(60) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) Methanesulfomide,
(61) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropyl-sulfonylamide,
(62) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) ethyl sulfonamide,
(63) N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) -2- methyl propanamide,
(64) N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) two Fluorakil 100 of -2,2-,
(65) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) urethanes,
(66) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyrrole Pyridine -2- base amino) piperidin-1-yl] ketone,
(67) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes,
(68) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (1,3- Thiazol-2-yl amino) piperidin-1-yl] ketone,
(69) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- is (phonetic Pyridine -2- base amino) piperidin-1-yl] ketone,
(70) [({ 6- [(2- methybutane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base } carbonyl) piperidin-4-yl] methyl carbamate,
(71) (4- hydroxy piperidine -1- base) [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] ketone,
(72) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid propyl ester,
(73) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(74) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(75) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(76) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(77) [({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base } carbonyl) piperidin-4-yl] methyl carbamate,
(78) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(79) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(80) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(81) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(82) N- (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide,
(83) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide,
(84) [1- ({ 6- [{ [1- (methoxy) cyclopropyl] methyl } (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(85) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(86) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(87) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(88) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(89) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) t-butyl carbamate,
(90) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(91) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- (dimethylamino) ethyl ester,
(92) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(93) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(94) 2- methoxyl group-N- (1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(95) N- (1- { [6- (2- ethyl-butoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(96) (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) methyl carbamate,
(97) (1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) methyl carbamate,
(98) N- [1- ({ 6- [(2- ethyl-butyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(99) N- (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(100) [({ 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base } carbonyl) piperidin-4-yl] methyl carbamate,
(101) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(102) N- (1- { [6- (2- ethyl-butoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) propionamide,
(103) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) propionamide,
(104) [({ 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] propionamide,
(105) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] { 4- [(3- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone,
(106) N- [1- ({ 6- [(2- methoxyl group -2- methyl-propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide,
(107) (4- hydroxy piperidine -1- base) { 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl } ketone,
(108) N- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) propionamide,
(109) N- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(110) N- (1- { [6- { [(2S) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(111) N- (1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(112) [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(113) [1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(114) [({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] propionamide,
(115) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] { 4- [(5- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone,
(116) 2- methyl-N- [1- ({ 6- [(2- methybutane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide,
(117) [({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] propionamide,
(118) [1- ({ 6- [tert-butyl (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(119) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid cyclopropyl ester,
(120) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid cyclopropyl ester,
(121) the fluoro- N- of 2,2- bis- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(122) 3- [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] -1,1- dimethyl urea,
(123) 3- (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -1,1- dimethyl urea,
(124) [1- ({ 6- [(3- methy oxetane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] carbamic acid propane -2- base ester,
(125) [1- ({ 6- [(bicyclic methyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(126) (1- { [6- phenoxy group -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) methyl carbamate,
(127) 4- [6- ({ 4- [(methoxycarbonyl) amino] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] amino } piperidines -1- carboxylic acid tert-butyl ester,
(128) (1- { [6- (piperidin-4-yl amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) methyl carbamate,
(129) [1- ({ 6- [(1- anocy clopropyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(130) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(131) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -5- methoxyl group -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(132) [1- ({ 6- [(2S)-butane -2- base amino] -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(133) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(134) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -5- ethyoxyl -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(135) (1- { [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- (pyridin-3-yl oxygroup) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) methyl carbamate.
(VII)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (I), wherein pyrrole Simultaneously thiazolium compounds is compound described in any one of following (1)~(58) to azoles:
(1) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(2) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(3) N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(4) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(5) N- [1- ({ 6- [({ 1- [(difluoro-methoxy) methyl] cyclopropyl } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(6) N- [1- ({ 6- [({ 1- [(difluoro-methoxy) methyl] cyclobutyl } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(7) N- [1- ({ 6- [({ 1- [(difluoro-methoxy) methyl] cyclopenta } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(8) N- [1- ({ 6- [({ 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrans -4- base } methyl) amino] -2- (pyrrole Azoles simultaneously [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(9) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(10) N- (1- [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(11) [({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(12) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(13) N- (1- [6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(14) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(15) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes,
(16) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide,
(17) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(18) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(19) N- (1- { [6- (cyclo propyl methoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(20) N- [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(21) N- (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(22) N- [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(23) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone,
(24) N- (1- { [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(25) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) methyl carbamate,
(26) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid propane -2- base ester,
(27) [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(28) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) ketone,
(29) (1- { [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(30) [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(31) (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) methyl carbamate,
(32) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropyl-sulfonylamide,
(33) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) ethyl sulfonamide,
(34) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) urethanes,
(35) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyrrole Pyridine -2- base amino) piperidin-1-yl] ketone,
(36) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid propyl ester,
(37) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide,
(38) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(39) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(40) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) t-butyl carbamate,
(41) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(42) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- (dimethylamino) ethyl ester,
(43) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(44) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(45) (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) methyl carbamate,
(46) N- [1- ({ 6- [(2- ethyl-butyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(47) N- (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(48) [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(49) [1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(50) [({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base } carbonyl) piperidin-4-yl] propionamide,
(51) [1- ({ 6- [tert-butyl (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(52) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) carbamic acid cyclopropyl ester,
(53) [1- ({ 6- [(3- methy oxetane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] carbamic acid propane -2- base ester,
(54) [1- ({ 6- [(1- anocy clopropyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] methyl carbamate,
(55) [1- ({ 6- [(2S)-butane -2- base amino] -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(56) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(57) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(58) (1- { [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- (pyridin-3-yl oxygroup) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) methyl carbamate.
(VIII)
Pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as described in (I), wherein pyrrole Simultaneously thiazolium compounds is compound described in any one of following (1)~(8) to azoles:
(1) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(2) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(3) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) methyl carbamate,
(4) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) urethanes,
(5) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(6) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(7) [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(8) [1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate.
(IX)
Medical composition, contain pyrazolo thiazolium compounds described in any one of (I)~(VIII) or its pharmaceutically Acceptable salt or its solvate are as effective component.
(X)
JAK1 inhibitor, contain pyrazolo thiazolium compounds described in any one of (I)~(VIII) or its pharmaceutically Acceptable salt or its solvate are as effective component.
(XI)
The therapeutic agent of diseases associated with inflammation, contain pyrazolo thiazolium compounds described in any one of (I)~(VIII) or Its pharmaceutically acceptable salt or its solvate are as effective component.
(XII)
Therapeutic agent as described in (XI), wherein diseases associated with inflammation is atopic dermatitis, eczema, bronchial asthma, acidophilia Granulocytic pneumonia, chronic obstructive pulmonary disease, allergic rhinitis, Eosinophilic's nasosinusitis, nasal polyp, rigid spine Scorching or Eosinophilic's esophagitis.
(XIII)
The therapeutic agent of autoimmune disease contains pyrazolo thiazole chemical combination described in any one of (I)~(VIII) Object or its pharmaceutically acceptable salt or its solvate are as effective component.
(XIV)
Therapeutic agent as described in (XIII), wherein autoimmune disease is rheumatoid arthritis, psoriatic arthritis Inflammation, juvenile arthritis, the graceful disease in Karst, systemic lupus erythematosus, xerodermosteosis, inflammatory bowel disease, psoriasis, sclerderm Disease, xerophthalmia, aorto-arteritis, giant cell arteritis, microscopic polyangitis, granulomatous Polyangiitis, acidophilia granulation Swollen property Polyangiitis or neuromyelitis optica.
(XV)
The therapeutic agent of proliferative diseases, contain pyrazolo thiazolium compounds described in any one of (I)~(VIII) or Its pharmaceutically acceptable salt or its solvate are as effective component.
(XVI)
Therapeutic agent as described in (XV), wherein proliferative diseases are solid carcinoma, blood cancer, lymphoid malignancies, bone Marrow proliferative diseases, Huppert's disease, pulmonary fibrosis or eosinophilia.
(XVII)
Diabetic nephropathy, alopecia areata, bone marrow transplant rejection or the therapeutic agent of organ transplantation rejection, contain (I)~(VIII) Any one of described in pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its solvate as effective component.
Hereinafter, being described in detail to the definition of each term used in this specification.
" halogen " indicates fluorine atom, chlorine atom, bromine atom or iodine atom.Particularly preferred fluorine atom.
As " alkyl ", can enumerate such as linear chain or branched chain has 1~10 carbon atoms, preferably 1~8 carbon originals The alkyl of sub, more preferable 1~6 carbon atoms.Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl can specifically be enumerated Base, sec-butyl, tert-butyl, amyl, sec-amyl, 1- ethyl propyl, 1,2- dimethyl propyl, tertiary pentyl, 2- methyl butyl, isoamyl Base, neopentyl, n-hexyl, Sec-Hexyl, 1- ethyl-butyl, isohesyl, new hexyl, 1,1- dimethylbutyl, 1,1,2- trimethyl Propyl, 2- ethyl-butyl, 1,2,2- thmethylpropyl, 2,2- dimethylbutyl, heptyl, different heptyl, octyl, iso-octyl etc..
As " (difluoro alkoxy) alkyl ", " alkoxyalkyl ", " dialkyl amido ", " dialkyl aminoalkyl ", " alkane Base carbonyl ", " halogenated alkyl ", " dihalo alkyl ", " tri haloalkyl " moieties, can enumerate same as described above " alkyl ".
" halogenated alkyl " indicates above-mentioned " alkyl " group obtained by 1 above-mentioned " halogen " substitution.It specifically can example citing A such as methyl fluoride, chloromethyl, a fluoro ethyl.
" dihalo alkyl " indicates above-mentioned " alkyl " group obtained by 2 above-mentioned " halogen " substitutions.It specifically can example citing Such as difluoromethyl, bis-fluoro ethyls, bis- fluoropropyl of 1,2-.
" tri haloalkyl " indicates above-mentioned " alkyl " group obtained by 3 above-mentioned " halogen " substitutions.It specifically can example citing Such as trifluoromethyl, trichloromethyl, trifluoroethyl.
As " alkoxy ", can enumerate such as linear chain or branched chain has 1~8 carbon atoms, preferably 1~6 carbon The alkoxy of atom.Methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, Zhong Ding can specifically be enumerated Oxygroup, tert-butoxy, n-pentyloxy, positive hexyloxy, positive oxygroup in heptan, n-octyloxy etc..
As " (difluoro alkoxy) alkyl ", the alkoxy portion of " alkoxyalkyl ", " alkane same as described above can be enumerated Oxygroup ".
As " naphthenic base ", the saturated hydrocarbyl for 1~3 ring that such as carbon number is 3~10 can be enumerated.It is preferred that carbon number 3 The naphthenic base of a~6 monocycles.Cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, two rings can specifically be enumerated [2.1.0] amyl, two rings [2.2.1] heptyl and two rings [2.2.2] octyl etc..
L1In " naphthenic base " more preferably with 3~6 carbon atoms monocycle naphthenic base, further preferred cyclopropyl Base.
As " naphthenic base " part of " cycloalkyl amino ", preferably cyclopropyl.
As " aryl ", aromatic hydrocarbyl that such as 1~3 ring can be enumerated, that carbon number is 6~14.It can specifically enumerate Phenyl, 1- naphthalene, 2- naphthalene, 1- anthryl, 2- anthryl, 9- anthryl, 1- phenanthryl, 2- phenanthryl, 3- phenanthryl, 4- phenanthryl, 10- phenanthryl Deng.Wherein, preferred phenyl.
As " heteroaryl ", the miscellaneous original in such as ring with 1~4 selected from nitrogen-atoms, sulphur atom, oxygen atom can be enumerated Son, 1~2 ring aromatic heterocycle being made of 5~10 ring member nitrogen atoms.Furyl (such as 2- furans can specifically be enumerated Base, 3- furyl), thienyl (such as 2- thienyl, 3- thienyl), pyrrole radicals (such as 2- pyrrole radicals, 3- pyrrole radicals), imidazoles Base (such as 2- imidazole radicals, 4- imidazole radicals), pyrazolyl (such as 3- pyrazolyl, 4- pyrazolyl), triazolyl (such as 1,2,4- tri- Azoles -3- base, 1,2,4- triazole -5- base, 1,2,3- triazole-4-yl), tetrazole radical (such as 5- tetrazole radical),Oxazolyl (such as 2-Oxazolyl, 4-Oxazolyl, 5-Oxazolyl), it is differentOxazolyl (such as 3- is differentOxazolyl, 4- are differentOxazolyl, 5- are differentOxazolyl), Di azoly (such as 1,3,4-Diazole -2- base), thiazolyl (such as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), thiadiazoles Base, isothiazolyl (such as 3- isothiazolyl, 4- isothiazolyl, 5- isothiazolyl), pyridyl group (such as 2- pyridyl group, 3- pyridine Base, 4- pyridyl group), pyridazinyl (such as 3- pyridazinyl, 4- pyridazinyl), (such as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- are phonetic for pyrimidine radicals Piperidinyl), pyrazinyl (such as 2- pyrazinyl), benzimidazolyl (such as 2- benzimidazolyl, 4- benzimidazolyl, 5- benzo miaow Oxazolyl, 6- benzimidazolyl, 7- benzimidazolyl), indazolyl (such as 3- indazolyl, 4- indazolyl, 5- indazolyl, 6- indazole Base, 7- indazolyl), isoquinolyl (such as 1- isoquinolyl, 3- isoquinolyl, 4- isoquinolyl, 5- isoquinolyl, 6- isoquinoline Quinoline base, 7- isoquinolyl, 8- isoquinolyl).It is preferred that furyl (such as 2- furyl, 3- furyl), imidazole radicals (such as 2- miaow Oxazolyl, 4- imidazole radicals), thiazolyl (such as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), pyridyl group (such as 2- pyridyl group, 3- Pyridyl group, 4- pyridyl group), pyridazinyl (such as 3- pyridazinyl, 4- pyridazinyl), pyrimidine radicals (such as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals), pyrazinyl (such as 2- pyrazinyl).
As R3In " heteroaryl ", preferred 3- pyridyl group.
As R8In " heteroaryl ", it is preferably differentOxazolyl (such as 3- is differentOxazolyl, 4- are differentOxazolyl, 5- are differentAzoles Base), thiazolyl (such as 2- thiazolyl, 4- thiazolyl, 5- thiazolyl), (such as 2- pyrimidine radicals, 4- pyrimidine radicals, 5- are phonetic for pyrimidine radicals Piperidinyl, 6- pyrimidine radicals), pyridyl group (2- pyridyl group, 3- pyridyl group, 4- pyridyl group), more preferable 3- is differentOxazolyl, 5- are differentAzoles Base, 2- thiazolyl, 2- pyrimidine radicals, 2- pyridyl group.
As L1In " heteroaryl ", more preferable thienyl (such as 2- thienyl, 3- thienyl), pyridyl group (such as 2- Pyridyl group, 3- pyridyl group, 4- pyridyl group).
As " saturated heterocyclyl ", can enumerate for example with 1~3 miscellaneous original selected from nitrogen-atoms, sulphur atom, oxygen atom Son, the saturated heterocyclyl being made of 3~8 ring member nitrogen atoms.Oxetanyl (such as 2- oxetanes can specifically be enumerated Base, 3- oxetanyl), azetidinyl (such as 2- azetidinyl, 3- azetidinyl), THP trtrahydropyranyl (such as 2- THP trtrahydropyranyl, 3- THP trtrahydropyranyl, 4- THP trtrahydropyranyl), pyrrolidinyl (such as 1- pyrrolidinyl, 2- pyrrolidines Base, 3- pyrrolidinyl), piperidyl (such as 2- piperidyl, 3- piperidyl, 4- piperidyl), piperazinyl (such as 2- piperazinyl, 3- Piperazinyl), morpholinyl (such as 2- morpholinyl, morpholinyl), thio-morpholinyl (such as 2- thio-morpholinyl, 3- thiomorpholine Base) or tetrahydrofuran base (2- tetrahydrofuran base, 3- tetrahydrofuran base).Can more preferably enumerate piperidyl (such as 2- piperidyl, 3- piperidyl, 4- piperidyl), tetrahydrofuran base (2- tetrahydrofuran base, 3- tetrahydrofuran base), THP trtrahydropyranyl (2- tetrahydro pyrrole Mutter base, 3- THP trtrahydropyranyl, 4- THP trtrahydropyranyl) etc..
Specific embodiment
The compounds of this invention can be according to such as method described below, aftermentioned embodiment or well known method, from public affairs Compound or the intermediate that can be readily synthesized are known to manufacture.In the manufacture of the compounds of this invention, raw material has and has an impact to reaction Substituent group in the case where, usually first pass through after well known method is protected raw material with protecting group appropriate and react in advance. Protecting group can be removed after the reaction by well known method.
Preparation method 1
[changing 2]
(in above-mentioned reaction equation, Z, R1、R2It is identical as above-mentioned definition.R11Indicate alkyl, R21Indicate hydrogen or alkyl, R22Table Show that alkyl, X indicate the leaving groups such as halogen.)
Process 1
This process is (such as can be according to Heterocycles, 2008,75,2005- by compound 1 with N- amino agent 2 The method recorded in 2012. synthesizes) N- amination, obtain N- aminothiazoleThe process of salt 3.
N- amino agent is different according to used solvent, but is not particularly limited, and such as O- (1,3,5- can be used Trimethylphenysulfonyl) azanol etc..
N- amino agent relative to the amount that compound 1 is 1~5 times of molar equivalent preferably to use.
As solvent used in this reaction, it is not particularly limited as long as being not involved in reaction, such as tetrahydro furan can be enumerated Mutter (hereinafter referred to as " THF "), diethyl ether, 1,4- bis-The ethers such as alkane, dimethoxy-ethane (hereinafter referred to as " DME "), acetonitrile, third The nitriles such as nitrile, the ketones such as acetone, the hydro carbons such as benzene, toluene, the halogenated hydrocarbons such as chloroform, methylene chloride, 1,2- dichloroethanes or it Mixed solvent.
Reaction temperature is -78 DEG C~100 DEG C, preferably -78 DEG C~50 DEG C.
Reaction time is different according to reaction temperature etc., and usually 10 minutes~24 hours.
Process 2
This process is to make N- aminothiazoleSalt 3 is reacted with ortho acid ester compounds 4, in a suitable solvent to be changed The process for closing object 5.
As solvent used in this reaction, it is not particularly limited as long as being not involved in reaction, such as THF, two can be enumerated Ether, 1,4- bis-The ethers such as alkane, DME, the nitriles such as acetonitrile, propionitrile, the ketones such as acetone, the hydro carbons such as benzene, toluene, chloroform, dichloro The halogenated hydrocarbons such as methane, 1,2- dichloroethanes or their mixed solvent.Alternatively, ortho acid esterification also can be used in this reaction It closes object 4 and is used as solvent.
Reaction temperature is 0 DEG C~200 DEG C, preferably 0 DEG C~150 DEG C.
Reaction time is different according to reaction temperature etc., and usually 10 minutes~24 hours.
Ortho acid ester compounds 4 are preferably relative to N- aminothiazoleSalt 3 is that the amount of 1~50 times of molar equivalent uses.
Process 3
This process is the process that itrile group is converted to amidine, for example, can according to Slee etc., J.Med.Chem.2008,51, 1719-1729. the method for middle record synthesizes.That is, be by compound 5 in the presence of the alkali of alkali metal alcoholates etc, closing It is stirred in suitable solvent, to be made into imidoate, reacts gained imidoate with ammonia or ammonium salt, to become amidification The process for closing object 6.
As alkali used in this reaction, the alcohol salt such as sodium methoxide, sodium ethoxide can be enumerated.
Alcohol salt relative to the amount that compound 5 is 1~5 times of molar equivalent preferably to use.
It as used solvent, is not particularly limited as long as being not involved in reaction, usually using alcohol such as methanol, ethyl alcohol Class.
In the manufacture of imidoate, reaction temperature is 0 DEG C~150 DEG C, preferably 0 DEG C~100 DEG C.
In the manufacture of imidoate, the reaction time is different according to reaction temperature etc., and usually 30 minutes~24 hours.
In the manufacture of amidine compound 6, as used ammonium salt, ammonium chloride, ammonium acetate etc. can be enumerated.
Used ammonium salt or ammonia relative to the amount that imidoate is 1~10 times of molar equivalent preferably to use.
It as used solvent, is not particularly limited as long as being not involved in reaction, usually using alcohol such as methanol, ethyl alcohol Class.
Reaction temperature is -78 DEG C~150 DEG C, preferably 0 DEG C~150 DEG C.
Reaction time is different according to reaction temperature etc., and usually 30 minutes~24 hours.
This reaction can also be manufactured by being directly added into ammonium salt into the reaction system for prepare imidoate.
Process 4
This process be make amidine compound 6 with oxaloacetic acid compound 7 or its salt in the presence of the alkali such as potassium hydroxide, closing Reaction, the process to obtain pyrimidine compound 8 in suitable solvent, such as can be according to the side recorded in WO2009/138712 Method synthesizes.
As used alkali, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, carbonic acid can be enumerated The inorganic bases such as potassium, cesium carbonate, the alcohol salt such as sodium methoxide, sodium ethoxide, potassium tert-butoxide.
Used alkali relative to the amount that amidine compound 6 is 1~50 times of molar equivalent preferably to use.
It as solvent used in this reaction, is not particularly limited as long as being not involved in reaction, such as THF, 1 can be used, 4- bis-The ethers such as alkane, DME, the alcohols such as methanol, ethyl alcohol, the ketones such as acetone, water or their mixed solvent.
In this reaction, reaction temperature is 0 DEG C~200 DEG C, preferably 0 DEG C~150 DEG C.
In this reaction, the reaction time is different according to reaction temperature etc., and usually 30 minutes~24 hours.
Process 5
This process is to make pyrimidine compound 8 in the presence of halogenating agent, is anti-at 0 DEG C~180 DEG C in a suitable solvent The process answered, compound 9 will be obtained after its halogenation, by the etheride esterification of generation.
In this halogenation, as used halogenating agent, phosphoryl chloride phosphorus oxychloride, phosphoryl bromide, phosphorus pentachloride can be enumerated.This reaction In, these halogenating agents can be used alone or as a mixture.
It can according to need in this halogenation using alkali.As used alkali, can enumerate diethylaniline, pyridine, 2,6- lutidines, N, N- diisopropylethylamine (hereinafter referred to as " DIPEA "), triethylamine (hereinafter referred to as " TEA ").
The dosage of halogenating agent and alkali is suitably 1~100 times of mole relative to pyrimidine compound 8.
As used solvent, it is not particularly limited as long as being not involved in reaction, such as THF, diethyl ether, 1 can be enumerated, 4- bis-The ethers such as alkane, DME, n,N-Dimethylformamide (hereinafter referred to as " DMF "), n,N-dimethylacetamide, N- methyl pyrrole The amides such as pyrrolidone (hereinafter referred to as " NMP "), the nitriles such as acetonitrile, propionitrile, the ketones such as acetone, the hydro carbons such as benzene, toluene, chloroform, The halogenated hydrocarbons such as methylene chloride, 1,2- dichloroethanes, sulfoxide types such as dimethyl sulfoxide (hereinafter referred to as " DMSO ") or theirs is mixed Bonding solvent.
Reaction temperature is 0 DEG C~200 DEG C, preferably 0 DEG C~150 DEG C.
Reaction time is different according to reaction temperature etc., and usually 10 minutes~48 hours.
This esterification can carry out by conventional method, as used alcohol (R22- OH), methanol, ethyl alcohol can be enumerated.
It can according to need in this esterification using alkali.As used alkali, can enumerate diethylaniline, pyridine, The organic bases such as 2,6- lutidines, DIPEA, TEA, the inorganic bases such as sodium bicarbonate.
The dosage of pure and mild alkali is suitably 1~100 times of mole relative to etheride.
In this esterification, as used solvent, it is not particularly limited, can be enumerated for example as long as being not involved in reaction THF, diethyl ether, 1,4- bis-The ethers such as alkane, DME, the amides such as DMF, n,N-dimethylacetamide, NMP, acetonitrile, propionitrile etc. Nitrile, the ketones such as acetone, the hydro carbons such as benzene, toluene, the halogenated hydrocarbons such as chloroform, methylene chloride, 1,2- dichloroethanes, the sulfoxides such as DMSO Class or their mixed solvent.In addition, the alcohol itself reacted can be used as solvent use.
Reaction temperature is -78 DEG C~200 DEG C, preferably 0 DEG C~50 DEG C.
Reaction time is different according to reaction temperature etc., and usually 10 minutes~48 hours.
Process 6
This process is to make compound 9 and (the alcoholic compound R of compound 103OH or amine compounds NHR4R5) in suitable solvent Middle reaction, the process that compound 11 is made.
In this reaction, the dosage of compound 10 is suitably 1~10 times of mole relative to compound 9.
It can according to need in this reaction and reacted in the presence of acids and bases.It, can example citing as used acid Such as hydrochloric acid, sulfuric acid inorganic acid, as used alkali, can enumerate such as TEA, DIPEA, n,N-Dimethylaniline, pyridine, The organic bases such as DMAP, 1,8- diazabicyclo [5.4.0] -7- hendecene, sodium hydroxide, potassium hydroxide, lithium hydroxide, bicarbonate The inorganic bases such as sodium, sodium carbonate, potassium carbonate, cesium carbonate, the alcohol such as sodium methoxide, sodium ethoxide, potassium tert-butoxide salt and sodium hydride, hydrogen Change the hydrogenated alkali metals such as potassium.
As used solvent, it is not particularly limited as long as being not involved in reaction, such as THF, diethyl ether, 1 can be enumerated, 4- bis-The ethers such as alkane, DME, the nitriles such as acetonitrile, propionitrile, the ketones such as acetone, the halogen such as chloroform, methylene chloride, 1,2- dichloroethanes For hydro carbons, the hydro carbons such as toluene, benzene, hexamethylene, the alcohols such as methanol, ethyl alcohol, isopropanol, butanol, DMF, n,N-dimethylacetamide, The amides such as NMP, the sulfoxide types such as DMSO or their mixed solvent.
In this reaction, reaction temperature is 0 DEG C~200 DEG C, preferably 0 DEG C~150 DEG C.Can according to need using microwave or Person carries out under air-proof condition.
Reaction time is different according to the type of raw material and alkali, reaction temperature etc., but it is normally suitable be 30 minutes~ In the range of 48 hours.
Process 7
This process is hydrolyzed ester compounds 11, in the presence of suitable acid or alkali, in a suitable solvent to obtain To the process of carboxylic acid 12.
In this reaction, as used acid, the inorganic acid of hydrochloric acid, sulfuric acid etc can be enumerated, trifluoroacetic acid is (hereinafter referred to as " TFA "), methanesulfonic acid, toluenesulfonic acid etc organic acid.As alkali, sodium hydroxide, potassium hydroxide, lithium hydroxide etc. can be enumerated Inorganic base.
In this reaction, the dosage of acid or alkali is suitably 1~10 times of mole relative to ester compounds 11.
As used solvent, be not particularly limited as long as being not involved in reaction, can enumerate such as water, methanol, ethyl alcohol, The alcohols such as isopropanol, THF, diethyl ether, Isosorbide-5-Nitrae-twoThe ethers such as alkane, DME, the nitriles such as acetonitrile, propionitrile, the ketones such as acetone, or Their mixed solvent.
In this reaction, reaction temperature is -78 DEG C~200 DEG C, preferably 0 DEG C~100 DEG C.
Reaction time is different according to reaction temperature etc., and usually 30 minutes~48 hours.
Process 8
This process is that carboxylic acid 12 is made to be condensed to yield reacting for compound [I] in a suitable solvent with compound 13.Pass through It reacts the carboxylic acid indicated with carboxylic acid 12 or its reactive compounds with compound 13, compound [I] can be manufactured.
As the reactive compounds of carboxylic acid 12, such as carboxylic acid halides (such as acyl chlorides, acylbromide), mixed acid anhydride, imidazoles can be enumerated Anion, active amide etc. are amide condensed to form substance usually used in reaction.
In the case where using carboxylic acid 12, as condensing agent, such as 1 can be used, 1 '-carbonyl dimidazoles, 1- ethyl -3- (3- Dimethylaminopropyl) carbodiimide (hereinafter referred to as " WSCD (water-soluble carbodiimide, Water Soluble Carbodiimide) "), N, N '-dicyclohexylcarbodiimide (hereinafter referred to as " DCC "), O- (7- azepine benzo triazol-1-yl)- 1,1,3,3- tetramethylurea hexafluorophosphoric acid ester (hereinafter referred to as " HATU "), O- (benzotriazole -1- base)-N, N, N ', N '-tetramethyl Urea hexafluorophosphoric acid ester (hereinafter referred to as " HBTU "), diethyl phosphorocyanidate, diphenyl phosphate azide, the chloro- 1- picoline of 2- 1H- benzotriazole -1- base oxygroup tripyrrole alkane subbase phosphonium iodide hexafluorophosphoric acid ester, three (dimethylamino of benzotriazole -1- base oxygroup Base) Phosphonium hexafluorophosphoric acid ester.
In this reaction, the dosage of condensing agent is suitably 1~3 times of mole relative to carboxylic acid 12.
It can according to need in this reaction and reacted in the presence of base.As used alkali, can enumerate for example TEA, DIPEA, N, the organic bases such as accelerine, pyridine, DMAP, 1,8- diazabicyclo [5.4.0] -7- hendecene.
In this reaction, I-hydroxybenzotriazole (hereinafter referred to as " HOBt "), n-hydroxysuccinimide can also be added Equal additives.
As used solvent, it is not particularly limited as long as being not involved in reaction, such as THF, diethyl ether, 1 can be enumerated, 4- bis-The ethers such as alkane, DME, the amides such as DMF, n,N-dimethylacetamide, NMP, the nitriles such as acetonitrile, propionitrile, the ketone such as acetone Class, the hydro carbons such as benzene, toluene, the halogenated hydrocarbons such as chloroform, methylene chloride or their mixed solvent.
Reaction temperature is -78 DEG C~200 DEG C, preferably -20 DEG C~50 DEG C.
Reaction time is different according to the type of raw material and condensing agent, reaction temperature etc., and usually 10 minutes~24 is small When.
Compound [I] can also be manufactured by preparation method 2 as shown below.
Preparation method 2
[changing 3]
(in above-mentioned reaction equation, Z, R1、R2It is identical as above-mentioned definition.X indicates halogen.)
Process 9
This process is using halogenating agents such as phosphoryl chloride phosphorus oxychlorides, reacts the hydroxylic moiety of compound 8 and halogen in a suitable solvent The process changed, obtain etheride 14 can be carried out similarly with process 5.
Process 10
This process is to react the etheride of compound 14 in a suitable solvent with amine compounds 13, to obtain acyl The process of amine compounds 15.
In this reaction, the dosage of compound 13 is suitably 1~3 times of mole relative to compound 14.
It can according to need in this reaction and reacted in the presence of base.As used alkali, can enumerate for example The organic bases such as TEA, DIPEA, n,N-Dimethylaniline, pyridine, DMAP, 1,8- diazabicyclo [5.4.0] -7- hendecene, carbon The inorganic bases such as sour hydrogen sodium, sodium carbonate, potassium carbonate, cesium carbonate.
As used solvent, it is not particularly limited as long as being not involved in reaction, such as THF, diethyl ether, 1 can be enumerated, 4- bis-The ethers such as alkane, DME, the nitriles such as acetonitrile, propionitrile, the ketones such as acetone, the halogen such as chloroform, methylene chloride, 1,2- dichloroethanes For hydro carbons, the hydro carbons such as toluene, benzene, hexamethylene, the amides such as DMF, n,N-dimethylacetamide, NMP, the sulfoxide types such as DMSO, or Their mixed solvent of person.
In this reaction, reaction temperature is -50 DEG C~100 DEG C, preferably 0 DEG C~50 DEG C.
Reaction time is different according to the type of raw material and alkali, reaction temperature etc., but normally suitable is 5 minutes~48 In the range of hour.
Process 11
This process is to make compound 15 and (the alcohol R of compound 103OH or amine body R4R5NH) react in a suitable solvent, The process for obtaining compound [I] can be carried out similarly with above-mentioned operation 6.
Pyrazolo thiazolium compounds of the invention can be used directly as medicine, also be can use well known method and be made The form of the solvate of pharmaceutically acceptable salt, solvate or salt come using.It, can as pharmaceutically acceptable salt Enumerate the salt of the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, richness The salt of the organic acids such as horse acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, methanesulfonic acid.
Solvate includes and the solvate of organic solvent, hydrate.It, can as pharmaceutically acceptable solvate Enumerate such as alcohol adduct (such as ethanolates can be enumerated), hydrate.As hydrate, such as monohydrate, two water can be enumerated Close object., can be with the solvent coordination of any kind and quantity when forming solvate, it can also be by pharmaceutically acceptable salt shape At solvate.
It, can be by the way that pyrazolo thiazolium compounds of the invention be dissolved such as in the case that the compounds of this invention is hydrochloride In the alcoholic solution of hydrogen chloride, the ethyl acetate solution of hydrogen chloride, hydrogen chloride 1,4- bis-The diethyl ether of alkane solution or hydrogen chloride Solution and obtain.
In the compounds of this invention, there is each stereoisomer of asymmetric carbon compound and their mixture includes In the present invention.Stereoisomer can use acid (tartaric acid, two of tool optical activity using its alkalinity by such as racemic modification Benzoyltartaric acid, mandelic acid, 10- camphorsulfonic acid etc.), optical resolution is carried out by well known method, or with previously prepared The compound of tool optical activity be that raw material manufactures.Furthermore it is also possible to optical resolution or asymmetric conjunction by using chiral column At manufacturing.In addition, each tautomer of the compound of tautomer can form and their mixture is all contained in this In invention.
The compounds of this invention has JAK1 inhibitory activity as shown in following test examples.In addition, the compounds of this invention is because of tool There is JAK1 inhibitory activity, so having anti-inflammatory effect, immunosuppressive action, inhibited proliferation etc..
Therefore, the compounds of this invention may be used as the relevant disease of such as JAK1, can be by anti-inflammatory effect, immunosupress Effect, inhibited proliferation etc. and the prophylactic or therapeutic agent for expecting the disease of validity.
As the disease specific that can apply the compounds of this invention, autoimmune disease (such as rheumatoid can be enumerated It is arthritis, psoriatic arthritis, juvenile arthritis, the graceful disease in Karst, systemic lupus erythematosus, xerodermosteosis, more Hair property sclerosis, inflammatory bowel disease, behcet's disease, myasthenia gravis, type-1 diabetes mellitus, immunoglobulin nephrosis, autoimmune first Shape adenopathy, psoriasis, chorionitis, lupus nephritis, xerophthalmia, vasculitis are (such as aorto-arteritis, giant cell arteritis, micro- Polyangiitis, granulomatous Polyangiitis, eosinophilic granuloma's property Polyangiitis under mirror), dermatomyositis, polymyositis, optic nerve Myelitis etc.), diseases associated with inflammation (such as atopic dermatitis, contact dermatitis, eczema, pruritus, food hypersenstivity, bronchus roar Asthma, Eosinophilic's pneumonia, chronic obstructive pulmonary disease, allergic rhinitis, chronic nasosinusitis, Eosinophilic's nasal sinus Inflammation, nasal polyp, allergic conjunctivitis, osteoarthritis, ankylosing spondylitis, Kawasaki disease, Buerger's disease, nodular polyarteritis, IgA vasculitis etc.), proliferative diseases it is (such as solid carcinoma, blood cancer, lymphoid malignancies, bone marrow proliferative diseases, more Hair property myeloma, pulmonary fibrosis, eosinophilia etc.), sudden deafness, diabetic nephropathy, alopecia areata, bone-marrow transplantation row Exclusive or organ transplantation rejection etc..
In the case that the compounds of this invention is administered as medicine, can by the compounds of this invention directly or as Contain such as 0.001%~99.5%, preferably 0.1%~90% doctor in pharmaceutically acceptable non-toxic and inert carrier Mammal including people is administered in drug composition.
As carrier, the diluent of solid, semisolid or liquid, filler and other prescription used additives can be enumerated More than one.Medical composition of the invention is preferably administered so that unit form is administered.In medical composition can be organized Administration, oral administration, intravenous administration, local administration (percutaneous dosing, eye drip, in intraperitoneal, thoracic cavity etc.) or by straight The mode of intestines is administered.Certainly, administration is carried out with being suitable for the dosage form of these medications.
Dosage as medicine is preferably to consider the state of the patients such as age, weight, the type of disease, degree, giving Whether medicine approach the type of the compounds of this invention, is to be adjusted on the basis of type of salt, salt etc., generally for adult Speech, with the compounds of this invention or the effective component meter of its pharmaceutically acceptable salt, in the case where oral administration, 1 day Dosage is suitably in the range of 0.01mg~5g/ adult, preferably in the range of 1mg~500mg/ adult.According to circumstances, Sometimes range amount below needs the dosage of the range or more instead sometimes.In general, be administered once within 1 day or in several times to Medicine, or in the case of intravenous administration, can be rapidly administered or be administered continuously within such as 24 hours.
More than one hydrogen, carbon and/or the other atoms of the compounds of this invention respectively can be by hydrogen, carbon and/or other originals The isotope of son replaces.As the example of this isotope, respectively include2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、123I and36Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, iodine and the chlorine of Cl etc.By the isotope instead of compound conduct Pharmaceuticals are also useful, all radioactive label bodies including the compounds of this invention.
Embodiment
Hereinafter, enumerating embodiment, test example and preparation example, the present invention will be described in more detail, but the present invention and unlimited Due to this.
In embodiment, abbreviation below is used.
DMF: dimethylformamide
DMSO: dimethyl sulfoxide
DIPEA:N, N- diisopropylethylamine
TEA: triethylamine
THF: tetrahydrofuran
TFA: trifluoroacetic acid
NMP:N- methyl pyrrolidone
HATU:O- (7- azepine benzo triazol-1-yl) -1,1,3,3- tetramethylurea hexafluorophosphoric acid ester
CDCl3: deuterated chloroform
DMSO-d6: deuterated dimethyl sulfoxide
MS: mass spectrum
LCMS: high performance liquid chromatography mass spectrum
ESI: electrospray ionisation method (Electron Spray Ionization)
M: molar concentration
MS is measured by LCMS.As ionization method, using ESI method.The mass spectrographic value observed is indicated with m/z.
The determination condition of LCMS is as described below.
Analysis instrument: ACQUITY UPLC MS/PDA system ((ウ ォ ー タ ー ズ society, water generation company) system)
Mass spectrograph: Waters 3100MS detector
Photodiode array detector: ACQUITY PDA detector (UV Detection wavelength: 210~400nm)
Column: Acquity BEH C18,1.7μm、2.1×50mm
Flow velocity: 0.5mL/ minutes
Column temperature: 40 DEG C
Solvent；
A liquid: 0.1% formic acid/H2O(v/v；Similarly hereinafter)
B liquid: 0.1% formic acid/acetonitrile
Microwave experiment is implemented with Biotage Initiator 60 (registered trademark).The temperature that can reach 40-250 DEG C, can Reach the pressure of 20 pas.
In this specification, specific rotatory power ([α]D) refer to that (it is high that hole field makes institute's (hole field makes institute) with such as optical activity meter Fast automatic polarimeter SEPA-200) etc. measurements specific rotatory power.
1 pyrazolo of reference example [5,1-b] [1,3] thiazole -7- formonitrile HCN
The manufacture of [process 1] 2- (thiazol-2-yl) acetonitrile
Lower 60% sodium hydride is gradually added on a small quantity ice-cold into DMF (100mL) solution of t-butylcyanoacetate (28g) (7.9g) is stirred 10 minutes.2- bromo thiazole (25g) is added thereto, is stirred at room temperature 15 minutes, is then stirred at 120 DEG C It mixes 2 hours.After 1M aqueous hydrochloric acid solution is added into reaction mixture, water layer is extracted with ethyl acetate.After organic layer is washed with water, It is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure.It is washed with hexane residue obtained, obtained solid object is suspended in toluene (200mL) is added p-methyl benzenesulfonic acid monohydrate (2.0g), stirs 2 hours at 105 DEG C.Reaction solution ethyl acetate is dilute After releasing, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation.Water layer is further extracted with ethyl acetate, combined organic layer is used After anhydrous magnesium sulfate is dry, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (7.0g).
MS (m/z): 125 [M+H]+
The manufacture of [process 2] pyrazolo [5,1-b] [1,3] thiazole -7- formonitrile HCN
Add under ice-cold into methylene chloride (50mL) solution of 2- obtained in process 1 (thiazol-2-yl) acetonitrile (5g) Enter O- (Base sulfonyl) azanol (such as according to Organic Process Research&Development, 2009,13, Recorded in 263-267. method synthesis) methylene chloride (20mL) solution, be stirred at room temperature 2 hours.Ice-cold lower to anti- It answers and diethyl ether is added in mixture, the solids that leaching is precipitated.Obtained solid object is suspended in triethyl orthoformate (35mL), It is stirred 1 hour at 120 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain title compound (2.5g)。
MS (m/z): 150 [M+H]+
2 6- hydroxyl -2- of reference example (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid
Into methanol (150mL) solution of [5,1-b] [1,3] thiazole -7- formonitrile HCN of pyrazolo obtained in reference example 1 (6g) 28% methanol solution of sodium methylate (24.6mL) is added, is stirred at room temperature 3 hours.Then, ammonium chloride (12.9g) is added, 90 It is stirred 1 hour at DEG C.Reaction solution is concentrated under reduced pressure, to the residue obtained middle 5M hydrogen that methyl-oxalacetic ester sodium (33.8g) is added Aqueous solution of sodium oxide (200mL), is stirred overnight at 100 DEG C.Concentrated hydrochloric acid is added into reaction mixture makes it in acidity, leaching The solids of precipitation.Obtained solid object is dissolved in 5M potassium hydroxide aqueous solution, uses chloroform.Concentrated hydrochloric acid is added into water layer The solids that it is precipitated in acidity, leaching, it is dry, obtain title compound (10g).
MS (m/z): 263 [M+H]+
The chloro- 2- of 3 6- of reference example (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester
By 6- hydroxyl -2- obtained in reference example 2 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (1.4g) is suspended in phosphoryl chloride phosphorus oxychloride (20mL), is added diethylaniline (1.6g), is stirred 2 hours at 130 DEG C.Reaction solution is subtracted Pressure concentration is stirred 10 minutes in ice-cold lower addition methanol (100mL) into reaction mixture.After reaction solution is diluted with chloroform, Add water to carry out liquid separation, further uses chloroform aqueous layer extracted.After the anhydrous magnesium sulfate drying of combined organic layer, depressurize dense Contracting.It is residue obtained to use silica gel chromatography, obtain title compound (910mg).
MS (m/z): 297 [M+H]+
4 6- hydroxy-5-methyl base -2- of reference example (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid
To methanol (6mL) solution of [5,1-b] [1,3] thiazole -7- formonitrile HCN of pyrazolo obtained in reference example 1 (300mg) 28% methanol solution of sodium methylate of middle addition (0.41mL), is stirred at room temperature 1 hour.Then, ammonium chloride (215mg) is added, It is stirred 2 hours at 70 DEG C.Reaction solution is concentrated under reduced pressure, is dissolved in 5M sodium hydrate aqueous solution (1.2mL), water for residue obtained (7mL) is added methoxalyl diethyl acetate (611mg), stirs 45 minutes at 90 DEG C.Dense salt is added into reaction mixture The solids that it is precipitated in acidity, leaching in acid, it is dry, obtain title compound (166mg).
MS (m/z): 277 [M+H]+
The chloro- 5- methyl -2- of 5 6- of reference example (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester
According to the method for reference example 3,6- hydroxy-5-methyl base -2- (pyrazolo [5,1-b] obtained in reference example 4 is used [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid replaces 6- hydroxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Carboxylic acid is synthesized, and title compound is obtained.
MS (m/z): 311 [M+H]+
Reference example 6 (2S) -1- (difluoro-methoxy) propane -2- amine hydrochlorate
The manufacture of [process 1] N- [(2S) -1- (difluoro-methoxy) propane -2- base] benzyq carbamate
Under an argon into the acetonitrile solution (40mL) of [(1S) -1- (hydroxymethyl) ethyl] benzyq carbamate (2g) 2,2- bis- fluoro- 2- (fluorosulfonyl) acetic acid (2.6g) and cupric iodide (364mg) is added, is stirred 30 minutes 1 hour at 50 DEG C.It will After reaction solution is diluted with ethyl acetate, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, water is further extracted with ethyl acetate Layer.Combined organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, it obtains Title compound (1.3g).
1H-NMR (CDCl3) δ: 1.23 (3H, d), 3.75-3.90 (2H, m), 4.00 (1H, bs), 4.82 (1H, bs), 5.11 (2H, s), 6.22 (1H, t), 7.30-7.40 (5H, m)
The manufacture of [process 2] (2S) -1- (difluoro-methoxy) propane -2- amine hydrochlorate
To the second of N- obtained in process 1 [(2S) -1- (difluoro-methoxy) propane -2- base] benzyq carbamate (1.3g) It is added in alcohol (40mL) solution 20% palladium dydroxide (being carried on active carbon, 300mg), pressure catalysis reduction in progress.Filtering reaction After liquid is to remove palladium, 4M hydrogen chloride-ethyl acetate solution (2mL) is added into mother liquor, solvent under reduced pressure is concentrated, is obtained titled It closes object (668mg).
1H-NMR (DMSO-d6) δ: 1.19 (3H, d), 3.40-3.50 (1H, m), 3.86 (1H, dd), 3.97 (1H, Dd), 6.77 (1H, t), 8.06 (3H, bs)
Reference example 7 (1S, 2S) -2- (difluoro-methoxy) cyclopentamine hydrochloride
The manufacture of [process 1] N- [(1S, 2S) -2- hydroxycyclopent base] benzyq carbamate
(the carrying of 20% palladium dydroxide is added into ethyl alcohol (40mL) solution of (1S, 2S) -2- benzyloxy cyclopentamine (5.0g) In active carbon, 1.0g), pressure catalysis reduction in progress.After palladium is filtered, solvent under reduced pressure is concentrated.To residue obtained middle addition water (100mL) and sodium carbonate (7.0g) is stirred at room temperature overnight in ice-cold lower addition benzyl chloroformate (6.7g).Extracted with chloroform Reaction mixture is taken, is concentrated under reduced pressure after anhydrous magnesium sulfate drying with saturated common salt water washing organic layer.It is residue obtained With silica gel chromatography, title compound (5.9g) is obtained.
MS (m/z): 236 [M+H]+
The manufacture of [process 2] N- [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] benzyq carbamate
According to the method for 6 process 1 of reference example, N- obtained in process 1 [(1S, 2S) -2- hydroxycyclopent base] amino is used Benzyl formate replaces [(1S) -1- (hydroxymethyl) ethyl] benzyq carbamate, obtains title compound.
1H-NMR (CDCl3) δ: 1.40-1.50 (1H, m), 1.62-1.88 (3H, m), 1.91-2.05 (1H, m), 2.10-2.25 (1H, m), 3.95-4.00 (1H, m), 4.40 (1H, bs), 4.72 (1H, bs), 5.10 (2H, dd), 6.33 (1H, t), 7.30-7.41 (5H, m)
The manufacture of [process 3] (1S, 2S) -2- (difluoro-methoxy) cyclopentamine hydrochloride
According to the method for 6 process 2 of reference example, [(1S, 2S) -2- (difluoro-methoxy) ring penta of N- obtained in process 2 is used Base] benzyq carbamate replaces N- [(2S) -1- (difluoro-methoxy) propane -2- base] benzyq carbamate to be synthesized, obtained To title compound.
1H-NMR (DMSO-d6) δ: 1.50-1.78 (4H, m), 2.01-2.10 (2H, m), 3.48 (1H, bs), 4.55 (1H, bs), 6.78 (1H, t), 8.28 (3H, bs)
Reference example 8 { 1- [(difluoro-methoxy) methyl] cyclopropyl } methylamine
DIPEA is added into methylene chloride (15mL) solution of [1- (amino methyl) cyclopropyl] methanol (720mg) (2.5mL) is stirred at room temperature overnight in ice-cold lower addition benzyl chloroformate (1.46g).Reaction solution is concentrated under reduced pressure, institute Residue silica gel chromatography is obtained, grease (348mg) is obtained.Into acetonitrile (10mL) solution of the grease (348mg) 2,2- bis- fluoro- 2- (fluorosulfonyl) acetic acid (395mg) and cupric iodide (56mg) is added, is stirred 1 hour at 50 DEG C.To reaction solution Middle addition saturated sodium bicarbonate aqueous solution carries out liquid separation, and water layer is further extracted with ethyl acetate.It is closed with saturated common salt water washing And organic layer, it is dry with anhydrous magnesium sulfate, be concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain grease (129mg).Be added into methanol (8.0mL) solution of the grease (129mg) 20% palladium dydroxide (be carried on active carbon, 43mg), pressure catalysis reduction in progress.After filtering reacting liquid is to remove palladium, mother liquor is concentrated under reduced pressure, obtains title compound (68mg)。
1H-NMR (CDCl3) δ: 0.51-0.52 (4H, m), 2.69 (2H, s), 3.79 (2H, s), 6.25 (1H, t)
Reference example 9 { 1- [(difluoro-methoxy) methyl] cyclobutyl } methylamine
According to the method for reference example 8, use [1- (amino methyl) cyclobutyl] methanol (such as according to Journal The method synthesis recorded in ofMedicinal Chemistry, 1972,15,1003-1006.) replace [1- (amino methyl) Cyclopropyl] methanol synthesized, obtain title compound.
1H-NMR (CDCl3) δ: 1.78-1.91 (6H, m), 2.78 (2H, s), 3.86 (2H, s), 6.23 (1H, t)
Reference example 10 { 1- [(difluoro-methoxy) methyl] cyclopenta } methylamine
According to the method for reference example 8, use [1- (amino methyl) cyclopenta] methanol (such as according to Journal The method synthesis recorded in ofMedicinal Chemistry, 1972,15,1003-1006.) replace [1- (amino methyl) Cyclopropyl] methanol synthesized, obtain title compound.
1H-NMR (CDCl3) δ: 1.42-1.46 (4H, m), 1.58-1.64 (4H, m), 2.69 (2H, s), 3.72 (2H, S), 6.24 (1H, t)
Reference example 11 { 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrans -4- base } methylamine
To the methylene chloride of 4- { [(tert-butoxycarbonyl) amino] methyl } tetrahydro -2H- pyrans -4- carboxylic acid, ethyl ester (1.3g) TFA (5.0mL) is added in (10mL) solution, is stirred at room temperature 4 hours.Reaction solution is concentrated under reduced pressure, to residue obtained DIPEA (3.1mL) is added in methylene chloride (10mL) solution to stir at room temperature in ice-cold lower addition benzyl chloroformate (1.1g) It mixes overnight.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain grease (1.4g).To the oily In ice-cold lower addition sodium borohydride (382mg) in ethyl alcohol (20mL) solution of object (1.3g), it is stirred at room temperature 2.5 days.Then, It is added sodium borohydride (382mg), is stirred at room temperature 4 hours, stirs 3 hours at 50 DEG C, be further stirred at room temperature Night.Water is added in the case where ice water is cooling into reaction solution, is extracted with ethyl acetate.After saturated common salt water washing organic layer, with nothing Water magnesium sulfate is dry, is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain grease (484mg).To the oily 2,2- bis- fluoro- 2- (fluorosulfonyl) acetic acid (463mg) and cupric iodide are added in acetonitrile (10mL) solution of object (484mg) (66mg) is stirred 1 hour at 50 DEG C.Saturated sodium bicarbonate aqueous solution is added into reaction solution, is extracted with ethyl acetate.With full It is dry with anhydrous magnesium sulfate after brine It organic layer, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, Obtain grease (209mg).20% palladium dydroxide is added into methanol (8.0mL) solution of the grease (200mg) (to be carried on Active carbon, 80mg), pressure catalysis reduction in progress.After filtering reacting liquid is to remove palladium, mother liquor is concentrated under reduced pressure, is obtained titled It closes object (108mg).
1H-NMR (CDCl3) δ: 1.50-1.53 (4H, m), 2.76 (2H, s), 3.64-3.71 (4H, m), 3.84 (2H, S), 6.24 (1H, t)
Reference example 12 (2R)-N, 3,3- triptane -2- amine hydrochlorate
TEA (15ml) is added into methylene chloride (100ml) solution of (2R) -3,3- dimethylbutane -2- amine (5.0g), In ice-cold lower dropwise addition benzyl chloroformate (9.3g), it is stirred overnight.After reaction mixture is diluted with chloroform, unsaturated carbonate hydrogen is added Sodium water solution carries out liquid separation, further uses chloroform aqueous layer extracted, after washing the organic layer merged with saturated sodium bicarbonate aqueous solution, It is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain thick product (4.0g).To Iodomethane (4.8g) is added in DMF (15ml) solution of the thick product of gained (4.0g), in 60% sodium hydride of ice-cold lower addition (748mg).After being stirred at room temperature 1 hour, ice water is added and is extracted with ethyl acetate.It has been washed with saturated sodium bicarbonate aqueous solution It is dry with anhydrous magnesium sulfate after machine layer, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain thick product (4.2g).Be added into ethyl alcohol (20mL) solution of the thick product of gained (4.2g) 20% palladium dydroxide (be carried on active carbon, 1.0g), pressure catalysis reduction in progress.After filtering reacting liquid is to remove palladium, 2M Hydrochlorine-Ethanol solution is added into mother liquor (9.0ml) is concentrated under reduced pressure to give title compound (2.0g).
MS (m/z): 116 [M-Cl]+
13 1- of reference example [1- (methoxy) cyclopropyl]-N- methyl methylamine hydrochloride
The manufacture of [process 1] { [1- (hydroxymethyl) cyclopropyl] methyl } benzyq carbamate
To [1- (amino methyl) cyclopropyl] methanol (1.5g) (such as according to Journal of Medicinal Recorded in Chemistry, 1972,15,1003-1006. method synthesis) methylene chloride (30mL) solution in DIPEA is added (3.7g) is stirred at room temperature overnight in ice-cold lower addition benzyl chloroformate (3.5g).Reaction solution is concentrated under reduced pressure, gained Residue silica gel chromatography obtains title compound (3.0g).
1H-NMR (CDCl3) δ: 0.46 (4H, s), 2.78 (1H, t), 3.20 (2H, d), 3.40 (2H, d), 5.12 (2H, S), 5.23 (1H, s), 7.35-7.37 (5H, m)
The manufacture of [process 2] { [1- (methoxy) cyclopropyl] methyl } methyl carbamic acid benzyl ester
To the DMF of { [1- (hydroxymethyl) cyclopropyl] methyl } benzyq carbamate (350mg) obtained in process 1 Iodomethane (1.0g), silver oxide (1.7g) are added in (3.0mL) solution, is stirred at room temperature overnight.Ice-cold lower mixed to reaction It closes in liquid and saturated aqueous ammonium chloride is added, extracted with diethyl ether.After organic layer anhydrous magnesium sulfate drying, depressurize dense Contracting.It is residue obtained to use silica gel chromatography, obtain title compound (189mg).
1H-NMR (CDCl3) δ: 0.46-0.60 (4H, m), 2.99 (3H, s), 3.15-3.36 (7H, m), 5.13 (2H, S), 7.28-7.39 (5H, m)
The manufacture of [process 3] 1- [1- (methoxy) cyclopropyl]-N- methyl methylamine hydrochloride
To { [1- (methoxy) cyclopropyl] methyl } methyl carbamic acid benzyl ester (165mg) obtained in process 2 Palladium dydroxide (being carried on active carbon, 80mg) is added in ethyl alcohol (6.0mL) solution, pressure catalysis reduction in progress.Filtering reacting liquid After removing palladium, 2M Hydrochlorine-Ethanol solution (27 μ L) is added into mother liquor, solvent under reduced pressure is concentrated, title compound is obtained (95mg)。
1H-NMR (DMSO-d6) δ: 0.53 (2H, t), 0.66 (2H, t), 2.51 (3H, s), 2.88 (2H, s), 3.26 (3H, s), 3.27 (2H, s), 8.52 (2H, br)
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 14 4- yl) methyl carbamate
The manufacture of [process 1] piperidin-4-yl methyl carbamate
TEA (9.2mL) is added into methylene chloride (100mL) solution of 1- benzyl piepridine -4- amine (5.0g), under ice-cold It is added dropwise methylchloroformate (2.6g), stirs 1 hour.After reaction solution is diluted with chloroform, adds water to carry out liquid separation, further use chloroform Aqueous layer extracted.After the anhydrous magnesium sulfate drying of combined organic layer, it is concentrated under reduced pressure, obtains grease (3.4g).To institute It obtains and is added 20% palladium dydroxide (being carried on active carbon, 1g) in ethyl alcohol (50mL) solution of grease (3.4g), press and urge in progress Change reduction.After filtering reacting liquid is to remove palladium, mother liquor is concentrated under reduced pressure, obtains title compound (1.9g).
MS (m/z): 159 [M+H]+
[process 2] (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines - 4- yl) methyl carbamate manufacture
By 6- hydroxyl -2- obtained in reference example 2 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (700mg) is suspended in phosphoryl chloride phosphorus oxychloride (5.0mL), is added diethylaniline (0.4g), is stirred 2 hours at 110 DEG C.By reaction solution It is concentrated under reduced pressure, is dissolved under ice-cold methylene chloride (40mL), piperidines -4- obtained in DIPEA (2.3mL) and process 1 is added Ylcarbamic acid methyl ester (443mg) is stirred at room temperature 30 minutes.After reaction solution is diluted with chloroform, unsaturated carbonate hydrogen is added Sodium water solution carries out liquid separation, further uses chloroform aqueous layer extracted.After the anhydrous magnesium sulfate drying of combined organic layer, subtracted Pressure concentration.It is residue obtained to use silica gel chromatography, obtain title compound (570mg).
MS (m/z): 421,423 [M+H]+
Reference example 15N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) cyclopropane carboxamide
According to the method for 14 process 2 of reference example, using N- (piperidin-4-yl) cyclopropane carboxamide (such as according to Jornal The method synthesis recorded in of Medicinal Chemistry, 2010,53,6386-6397.) replace piperidin-4-yl amino Methyl formate is synthesized, and title compound is obtained.
MS (m/z): 431,433 [M+H]+
Reference example 16N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) -2- methyl propanamide
According to the method for 14 process 2 of reference example, using 2- methyl-N- (4- piperidyl) propionamide (such as according to The method synthesis recorded in Bioorganic&Medicinal Chemistry Letters, 2012,22,3157-3162) carry out generation TEPA pyridine -4- ylcarbamic acid methyl ester is synthesized, and title compound is obtained.
MS (m/z): 433,435 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 17 4- yl) t-butyl carbamate
According to the method for 14 process 2 of reference example, piperidin-4-yl is replaced using N- (4- piperidyl) t-butyl carbamate Methyl carbamate is synthesized, and title compound is obtained.
MS (m/z): 463,465 [M+H]+
Reference example 18 [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyridine -2- base Amino) piperidin-1-yl] ketone
Under an argon into THF (3.0mL) solution of 1- benzyl piepridine -4- amine (980mg) and 2- fluorine pyridine (500mg) Bis- (trimethylsilyl) lithium amides (THF solution, 10.3mL) of 1M are added at -78 DEG C.It is stirred at room temperature 1 hour, then It is stirred overnight at 70 DEG C.After reaction mixture is diluted with chloroform, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, into one Step chloroform aqueous layer extracted.After the anhydrous magnesium sulfate drying of combined organic layer, it is concentrated under reduced pressure.It is residue obtained to use silica gel Column chromatography purifying, obtains grease (155mg).20% hydrogen is added into ethyl alcohol (10mL) solution of gained grease (150mg) Palladium oxide (being carried on active carbon, 50mg) and TFA (1 drop), the pressure catalysis reduction in progress at 40 DEG C.Filtering reacting liquid is to remove After palladium, mother liquor is concentrated under reduced pressure, obtains solids (110mg).By 6- hydroxyl -2- (pyrazolo [5,1- obtained in reference example 2 B] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (150mg) is suspended in phosphoryl chloride phosphorus oxychloride (1.1mL), it is added diethylaniline (85mg), It is stirred 2 hours at 110 DEG C.Reaction solution is concentrated under reduced pressure, is dissolved under ice-cold methylene chloride (10mL), DIPEA is added (0.5mL) and above-mentioned solids (101mg), is stirred at room temperature 30 minutes.After reaction solution is diluted with chloroform, saturated carbon is added Sour hydrogen sodium water solution carries out liquid separation, further uses chloroform aqueous layer extracted.After the anhydrous magnesium sulfate drying of combined organic layer, into Row is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (36mg).
MS (m/z): 400,402 [M+H]+
Reference example 19 [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (1,3- thiazole - 2- base amino) piperidin-1-yl] ketone
Under an argon to N- thiazol-2-yl t-butyl carbamate (1.9g) and 4- hydroxy piperidine -1- carboxylic acid tert-butyl ester In ice-cold lower addition diethylazodicarboxylate (2.2M toluene solution, 5.1mL) in THF (20mL) solution of (1.8g), in room Temperature lower stirring 16 hours.Solvent is evaporated off, it is residue obtained to use silica gel chromatography, obtain solids 1 (2.2g).To obtained solid TFA (5mL) is added in methylene chloride (5mL) solution of object 1 (2.2g), is stirred at room temperature 30 minutes 1 hour.Reaction solution is subtracted Pressure concentration, it is residue obtained to use silica gel chromatography, obtain solids 2 (796mg).By 6- hydroxyl -2- obtained in reference example 2 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (100mg) is suspended in phosphoryl chloride phosphorus oxychloride (1.1mL), and diethyl is added Aniline (57mg) stirs 2 hours at 110 DEG C.After reaction solution is concentrated under reduced pressure, methylene chloride is dissolved under ice-cold (10mL) is added DIPEA (0.33mL) and above-mentioned solids 2 (136mg), is stirred at room temperature 30 minutes.By reaction solution chlorine After imitative dilution, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, further uses chloroform aqueous layer extracted.Combined organic layer is used After anhydrous magnesium sulfate is dry, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (70mg).
MS (m/z): 446,448 [M+H]+
Reference example 20 [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyrimidine -2-base Amino) piperidin-1-yl] ketone
Add into methylene chloride (3.0mL) solution of 4- (pyrimidine -2 --amino) piperidines-1- carboxylic acid tert-butyl ester (251mg) Enter TFA (1.0mL), is stirred at room temperature 30 minutes.Solvent under reduced pressure is concentrated, it is residue obtained to use silica gel chromatography, it obtains Solids (248mg).By 6- hydroxyl -2- obtained in reference example 2 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Carboxylic acid (100mg) is suspended in phosphoryl chloride phosphorus oxychloride (1.1mL), is added diethylaniline (57mg), is stirred 1 hour at 110 DEG C.It will reaction It after solution is concentrated under reduced pressure, is dissolved under ice-cold methylene chloride (10mL), DIPEA (0.33mL) and above-mentioned solids is added (134mg) is stirred at room temperature 30 minutes.After reaction solution is diluted with chloroform, saturated sodium bicarbonate aqueous solution is added and is divided Liquid further uses chloroform aqueous layer extracted.After the anhydrous magnesium sulfate drying of combined organic layer, it is concentrated under reduced pressure.Gained is residual Slag silica gel chromatography obtains title compound (104mg).
MS (m/z): 441,443 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 21 4- yl) carbamic acid cyclopropyl ester
The manufacture of [process 1] 4- (cyclopropane carbonyl amino) piperidines -1- benzyl carboxylate
It is added into toluene (3mL) solution of 1- benzyloxycarbonylpiperid -4- carboxylic acid (400mg) TEA (0.85mL) and folded Nitrogen diphenyl phosphate (627mg) stirs 3 hours at 90 DEG C.Then, cyclopropyl alcohol (132mg) is added (such as according to US2012/ The method synthesis recorded in 0010183), it is stirred overnight at 80 DEG C.After reaction mixture is diluted with ethyl acetate, it is added full Liquid separation is carried out with sodium bicarbonate aqueous solution, water layer is further extracted with ethyl acetate.By combined organic layer anhydrous magnesium sulfate After drying, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (190mg).
MS (m/z): 319 [M+H]+
The manufacture of [process 2] piperidin-4-yl carbamic acid cyclopropyl ester
Ethyl alcohol (10mL) to (cyclopropane carbonyl amino) piperidines -1- benzyl carboxylate of 4- obtained in process 1 (190mg) is molten It is added in liquid 20% palladium dydroxide (being carried on active carbon, 50mg), pressure catalysis reduction in progress.Filtering reacting liquid is to remove palladium Afterwards, mother liquor is concentrated under reduced pressure, obtains title compound (110mg).
MS (m/z): 185 [M+H]+
[process 3] (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines - 4- yl) carbamic acid cyclopropyl ester manufacture
According to the method for 14 process 2 of reference example, piperidin-4-yl carbamic acid ring obtained in 21 process 2 of reference example is used Propyl ester replaces the piperidin-4-yl methyl carbamate to be synthesized, and obtains title compound.
MS (m/z): 447,449 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 22 4- yl) carbamic acid propane -2- base ester
According to the method for 14 process 2 of reference example, using piperidin-4-yl carbamic acid propane -2- base ester (such as according to The method synthesis recorded in US5082847) replace the piperidin-4-yl methyl carbamate to be synthesized, obtain title compound.
MS (m/z): 449,451 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 23 4- yl) carbamic acid propyl ester
According to the method for 14 process 2 of reference example, using piperidin-4-yl carbamic acid propyl ester (such as according in US5082847 The method of record synthesizes) replace piperidin-4-yl methyl carbamate to be synthesized, obtain title compound.
MS (m/z): 449,451 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 24 4- yl) carbamic acid 2- methoxy acrylate
The manufacture of [process 1] piperidin-4-yl carbamic acid 2- methoxy acrylate
TEA (556 μ L), nitrine are added into toluene (2mL) solution of 1- benzyloxycarbonylpiperid -4- carboxylic acid (300mg) Diphenyl phosphate (320 μ L), 2-methyl cellosolve (2mL), are stirred 4 hours at 100 DEG C.Reaction solution is concentrated under reduced pressure, gained Residue silica gel chromatography obtains grease (189mg).Into methanol (10mL) solution of gained grease (189mg) It is added 5% palladium (being carried on active carbon, 30mg), pressure catalysis reduction in progress.After filtering reacting liquid is to remove palladium, mother liquor is depressurized Concentration, obtains title compound (111mg).
1H-NMR (CDCl3) δ: 1.32-1.37 (2H, m), 1.94-1.97 (2H, m), 2.60-2.74 (2H, t), 3.08 (2H, d), 3.40 (3H, s), 3.57-3.59 (3H, m), 4.20-4.22 (2H, m), 4.75-4.77 (1H, m)
[process 2] (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines - 4- yl) carbamic acid 2- methoxy acrylate manufacture
According to the method for 14 process 2 of reference example, piperidin-4-yl carbamic acid 2- methoxyl group second obtained in process 1 is used Ester replaces the piperidin-4-yl methyl carbamate to be synthesized, and obtains title compound.
MS (m/z): 465,467 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 25 4- yl) carbamic acid 2,2- difluoro ethyl ester
The manufacture of [process 1] piperidin-4-yl carbamic acid 2,2- difluoro ethyl ester
Into methylene chloride (1.0mL) solution of 2,2- difluoroethanol (100mg) in ice-cold lower addition TEA (255 μ L), three Phosgene (145mg).After stirring 30 minutes, it is added 4- amino -1- benzyl piepridine (497 μ L), futher stirs 30 minutes.To reaction Saturated sodium bicarbonate aqueous solution is added in liquid, is extracted with ethyl acetate.After organic layer anhydrous magnesium sulfate drying, depressurized Concentration.It is residue obtained to use silica gel chromatography, obtain grease (185mg).To the methanol of gained grease (185mg) It is added in (10mL) solution 5% palladium (being carried on active carbon, 30mg), pressure catalysis reduction in progress.Filtering reacting liquid is to remove palladium Afterwards, mother liquor is concentrated under reduced pressure, obtains title compound (123mg).
1H-NMR (CDCl3) δ: 1.25-1.34 (2H, m), 1.94-1.97 (2H, m), 2.60-2.71 (2H, m), 3.04-3.08 (2H, m), 3.55-3.68 (1H, m), 4.20-4.35 (2H, m), 4.77 (1H, br), 5.78-6.08 (1H, m)
[process 2] (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines - 4- yl) carbamic acid 2,2- difluoro ethyl ester manufacture
According to the method for 14 process 2 of reference example, piperidin-4-yl carbamic acid 2 obtained in process 1,2- difluoro second are used Ester replaces the piperidin-4-yl methyl carbamate to be synthesized, and obtains title compound.
MS (m/z): 471,473 [M+H]+
(1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-of reference example 26 4- yl) carbamic acid 2,2,2- trifluoro ethyl ester
According to the method for reference example 25, replaces 2,2- difluoroethanol to be synthesized using 2,2,2- trifluoroethanols, obtain Title compound.
MS (m/z): 489,491 [M+H]+
Reference example 27N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) -2- methoxyl acetamide
The manufacture of [process 1] 2- methoxyl group-N- (4- piperidyl) acetamide
To in methylene chloride (200mL) solution of 1- benzyl piepridine -4- amine (10g) and TEA (15.9mL) in ice-cold lower drop Add methoxyacetyl chloride (6.3g), stirs 3 hours.Saturated sodium bicarbonate aqueous solution is added into reaction solution, is extracted with ethyl acetate It takes.After the anhydrous sodium sulfate drying of combined organic layer, it is concentrated under reduced pressure, obtains grease.Gained grease silica gel Column chromatography purifying, obtains grease (13.8g).20% palladium dydroxide is added into ethyl alcohol (100mL) solution of gained grease (being carried on active carbon, 1.0g), pressure catalysis reduction in progress.After filtering reacting liquid is to remove palladium, mother liquor is concentrated under reduced pressure, is obtained Title compound (8.0g).
MS (m/z): 173 [M+H]+
[process 2] N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) -2- methoxyl acetamide manufacture
According to the method for 14 process 2 of reference example, 2- methoxyl group-N- (4- piperidyl) acetamide obtained in process 1 is used It replaces the piperidin-4-yl methyl carbamate to be synthesized, obtains title compound.
MS (m/z): 435,437 [M+H]+
Reference example 28N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) two Fluorakil 100 of -2,2-
The manufacture of [process 1] 2,2- bis- fluoro- N- (4- piperidyl) acetamide
DMF (0.1mL) is added into methylene chloride (100mL) solution of difluoroacetic acid (2.3g), in ice-cold lower dropwise addition grass Acyl chlorides (2.6g) stirs 1 hour.Then, 1- benzyl piepridine -4- amine (3.0g) is added, in ice-cold lower dropwise addition TEA (6.1g), It stirs 1 hour at room temperature.Saturated sodium bicarbonate aqueous solution is added into reaction solution, is extracted with ethyl acetate.By organic layer nothing After aqueous sodium persulfate is dry, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain grease (500mg).To gained It is added 20% palladium dydroxide (being carried on active carbon, 300mg) in ethyl alcohol (5.0mL) solution of grease, pressure catalysis is gone back in progress It is former.After filtering reacting liquid is to remove palladium, mother liquor is concentrated under reduced pressure, obtains title compound (200mg).
MS (m/z): 179 [M+H]+
[process 2] N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) -2,2- two Fluorakil 100 manufacture
According to the method for 14 process 2 of reference example, the fluoro- N- of 2,2- bis- (4- piperidyl) acetamide obtained in process 1 is used It replaces the piperidin-4-yl methyl carbamate to be synthesized, obtains title compound.
1H-NMR (CDCl3) δ: 1.55-1.65 (4H, m), 2.04-2.15 (2H, m), 3.03-3.06 (1H, m), 3.28-3.30 (1H, m), 4.72-4.75 (1H, m) 5.91 (1H, t), 6.22-6.24 (1H, m) 7.09 (1H, d), 7.30 (1H, s), 7.90 (1H, d), 8.50 (1H, s)
Reference example 29 [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- hydroxy piperidine -1- Base) ketone
According to the method for 14 process 2 of reference example, piperidin-4-yl methyl carbamate is replaced to carry out using piperidines -4- alcohol Synthesis, obtains title compound.
MS (m/z): 364,366 [M+H]+
Reference example 30 (4- { [tert-butyl (dimethyl) silylation] oxygroup } piperidin-1-yl) [the chloro- 2- of 6- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone
According to the method for 14 process 2 of reference example, using 4- { [tert-butyl (dimethyl) silylation] oxygroup } piperidines (such as by According to the method synthesis recorded in WO2004/006926) replace the piperidin-4-yl methyl carbamate to be synthesized, obtain title Compound.
1H-NMR (CDCl3) δ: 0.07 (6H, d), 0.91 (9H, s), 1.56-1.75 (2H, m), 1.79-1.91 (2H, M), 3.40-3.50 (1H, m) 3.63-3.92 (3H, m), 4.02-4.11 (1H, m) 7.07 (1H, d), 7.26 (1H, s), 7.88 (1H, d), 8.51 (1H, s)
Reference example 31N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) propionamide
According to the method for 14 process 2 of reference example, using N- (4- piperidyl) propionamide (such as according to Bioorganic& The method synthesis recorded in Medicinal Chemistry Letters, 2003,13,2303-2306.) replace piperidines -4- Ylcarbamic acid methyl ester is synthesized, and title compound is obtained.
MS (m/z): 419,421 [M+H]+
Reference example 32 [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] { 4- [(3- fluorine pyridine - 2- yl) amino] piperidin-1-yl } ketone
The manufacture of [process 1] N- (1- benzyl piepridine -4- base) -3- fluorine pyridine -2- amine
Into DMSO (2.0mL) solution of 1- benzyl piepridine -4- amine (100mg) be added 2,3- difluoro pyridine (25 μ L), DIPEA (95 μ L) is stirred 2 hours at 130 DEG C with microwave reaction device.After reaction solution is diluted with ethyl acetate, add water into Row liquid separation, is further extracted with ethyl acetate water layer.After the anhydrous magnesium sulfate drying of combined organic layer, depressurize dense Contracting.It is residue obtained to use silica gel chromatography, obtain title compound (74mg).
MS (m/z): 286 [M+H]+
The manufacture of [process 2] 3- fluoro- N- (piperidin-4-yl) pyridine -2- amine
Ethyl alcohol (15mL) to N- obtained in process 1 (1- benzyl piepridine -4- base) -3- fluorine pyridine -2- amine (970mg) is molten 20% palladium dydroxide (being carried on active carbon, 300mg) is added in liquid, the TFA of catalytic amount is added, pressure catalysis reduction in progress. After filtering reacting liquid is to remove palladium, mother liquor is concentrated under reduced pressure, obtains title compound (770mg).
MS (m/z): 196 [M+H]+
[process 3] [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] { 4- [(3- fluorine pyridine - 2- yl) amino] piperidin-1-yl ketone manufacture
According to the method for 14 process 2 of reference example, 3- obtained in process 2 fluoro- N- (piperidin-4-yl) pyridine -2- amine is used It replaces the piperidin-4-yl methyl carbamate to be synthesized, obtains title compound.
MS (m/z): 458,460 [M+H]+
33 3- of reference example (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) -1,1- dimethyl urea
The manufacture of [process 1] 3- (1- benzyl piepridine -4- base) -1,1- dimethyl urea
TEA (4.4mL) is added into methylene chloride (50mL) solution of 1- benzyl piepridine -4- amine (2.0g), then in ice N is slowly added dropwise under cold, N- dimethylcarbamyl chloride (1.2mL) is stirred at room temperature overnight.Water is added into reaction mixture Afterwards, it is extracted with chloroform.After organic layer anhydrous magnesium sulfate drying, it is concentrated under reduced pressure, obtains title compound (2.7g).
1H-NMR (CDCl3) δ: 1.43 (2H, q), 1.94 (2H, d), 2.13 (2H, t), 2.80 (2H, d), 2.88 (6H, S), 3.50 (2H, s), 3.67 (1H, m), 4.17 (1H, d), 7.22-7.32 (5H, m)
The manufacture of [process 2] 1,1- dimethyl -3- piperidin-4-yl urea
According to the method for 21 process 2 of reference example, 3- obtained in process 1 (1- benzyl piepridine -4- base) -1,1- diformazan is used Base urea replaces 4- (cyclopropane carbonyl amino) piperidines -1- benzyl carboxylate to be synthesized, and obtains title compound.
MS (m/z): 172 [M+H]+
[process 3] 3- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) -1,1- dimethyl urea manufacture
According to the method for 14 process 2 of reference example, carry out generation using 1,1- dimethyl -3- piperidin-4-yl urea obtained in process 2 TEPA pyridine -4- ylcarbamic acid methyl ester is synthesized, and title compound is obtained.
MS (m/z): 434,436 [M+H]+
Reference example 34 [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] { 4- [(5- fluorine pyridine - 2- yl) amino] piperidin-1-yl } ketone
The manufacture of [process 1] N- (1- benzyl piepridine -4- base) -5- fluorine pyridine -2- amine
According to the method for 32 process 1 of reference example, replaces 2,3- difluoro pyridine to be synthesized using 2,5- difluoro pyridine, obtain To title compound.
MS (m/z): 286 [M+H]+
The manufacture of [process 2] 5- fluoro- N- (piperidin-4-yl) pyridine -2- amine
According to the method for 32 process 2 of reference example, N- obtained in process 1 (1- benzyl piepridine -4- base) -5- fluorine pyrrole is used Pyridine -2- amine replaces N- (1- benzyl piepridine -4- base) -3- fluorine pyridine -2- amine to be synthesized, and obtains title compound.
1H-NMR (CDCl3) δ: 1.75 (2H, d), 2.24 (2H, d), 2.99 (2H, t), 3.40 (2H, d), 3.97 (1H, S), 4.28 (2H, d), 6.36 (1H, d), 7.19 (1H, t), 7.93 (1H, d)
[process 3] [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] { 4- [(5- fluorine pyridine - 2- yl) amino] piperidin-1-yl ketone manufacture
According to the method for 14 process 2 of reference example, 5- obtained in process 2 fluoro- N- (piperidin-4-yl) pyridine -2- amine is used It replaces the piperidin-4-yl methyl carbamate to be synthesized, obtains title compound.
MS (m/z): 458,460 [M+H]+
(the 1- { [6- chloro-5-methoxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] of reference example 35 Carbonyl } piperidin-4-yl) methyl carbamate
[process 1] 6- hydroxy-5-methyl oxygroup -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid, ethyl ester Manufacture
To 60% sodium hydride is added in THF (10mL) solution of methoxyacetic acid (1.0g) and diethy-aceto oxalate (1.24g) (372mg) and ethyl alcohol (1 drop), are stirred at room temperature 6 hours.Reaction solution is concentrated under reduced pressure, solids is obtained.On the other hand, to 28% is added in methanol (300mL) solution of [5,1-b] [1,3] thiazole -7- formonitrile HCN of pyrazolo obtained in reference example 1 (10g) Methanol solution of sodium methylate (41mL) is stirred at room temperature 1 hour.Then, ammonium chloride (21.5g) is added, it is small that 2 is stirred at 80 DEG C When.Reaction solution is concentrated under reduced pressure, is dissolved in ethyl alcohol (5mL) for residue obtained, be added above-mentioned solids ethyl alcohol (5mL) solution, Sodium ethoxide (576mg), is stirred overnight at 80 DEG C.A small amount of acetic acid is added into reaction mixture to be concentrated under reduced pressure, by institute After obtaining residue with ethyl acetate dilution, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation.Water is further extracted with ethyl acetate Layer is concentrated under reduced pressure after the anhydrous magnesium sulfate drying of combined organic layer.It is residue obtained to use silica gel chromatography, it obtains To title compound (119mg).
MS (m/z): 321 [M+H]+
The system of [process 2] 6- hydroxy-5-methyl oxygroup -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid It makes
To 6- hydroxy-5-methyl oxygroup -2- obtained in process 1 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Lithium hydroxide monohydrate (60mg) is added in the THF (2mL) of carboxylic acid, ethyl ester (115mg), water (1mL) solution, is stirred at 60 DEG C It mixes 6 hours.It after addition 1M aqueous hydrochloric acid solution is neutralized into reaction mixture, is concentrated under reduced pressure, simultaneously leaching is washed with water Residue obtained, heat drying, obtains title compound (73mg) under reduced pressure.
MS (m/z): 293 [M+H]+
[process 3] (1- { [6- chloro-5-methoxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) methyl carbamate manufacture
According to the method for 14 process 2 of reference example, using 6- hydroxy-5-methyl oxygroup -2- obtained in process 2 (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid replaces the 6- hydroxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) phonetic Pyridine -4- carboxylic acid is synthesized, and title compound is obtained.
MS (m/z): 451,453 [M+H]+
(the 1- { [the chloro- 5- ethyoxyl -2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] of reference example 36 Carbonyl } piperidin-4-yl) methyl carbamate
The system of [process 1] 6- hydroxyl -5- ethyoxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid It makes
Diethy-aceto oxalate (1.1g) and 60% hydrogenation are added into THF (10mL) solution of 2- ethoxy ethyl acetate (1g) Sodium (333mg), is subsequently added into the ethyl alcohol of catalytic amount, is stirred at room temperature overnight.Reaction mixture is concentrated under reduced pressure, by gained Residue is suspended in sodium hydroxide (762mg) and water (10mL).
To methanol (10mL) solution of [5,1-b] [1,3] thiazole -7- formonitrile HCN of pyrazolo obtained in reference example 1 (406mg) 28% methanol solution of sodium methylate of middle addition (1.7mL), is stirred at room temperature 1 hour.Then, ammonium chloride (873mg) is added, 80 It is stirred 2 hours at DEG C.Reaction mixture is concentrated under reduced pressure, to the residue obtained middle above-mentioned suspension of addition, stirs 10 at 100 DEG C Hour.The solids that it is precipitated in acidity, leaching in concentrated hydrochloric acid is added into reaction mixture, it is dry, obtain title compound (217mg)。
MS (m/z): 307 [M+H]+
[process 2] (1- { [the chloro- 5- ethyoxyl -2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) methyl carbamate manufacture
According to the method for 14 process 2 of reference example, using 6- hydroxyl -5- ethyoxyl -2- obtained in process 1 (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid replaces the 6- hydroxyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) phonetic Pyridine -4- carboxylic acid is synthesized, and title compound is obtained.
MS (m/z): 465,467 [M+H]+
37 6- of reference example { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carboxylic acid
[process 1] 6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylate methyl ester manufacture
To the chloro- 2- of 6- obtained in reference example 3 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester (2S) -1- (difluoro-methoxy) propane -2- amine hydrochlorate obtained in reference example 6 is added in DMF (0.5mL) solution of (30mg) (21mg) and DIPEA (0.1mL) is stirred 3 hours at 100 DEG C.With silica gel chromatography reaction mixture, obtain titled It closes object (22mg).
MS (m/z): 384 [M+H]+
[process 2] 6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid manufacture
To 6- obtained in process 1 { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) THF (3mL) of pyrimidine -4- carboxylate methyl ester (15mg), lithium hydroxide one is added in water (1mL) solution Hydrate (5mg) stirs 2 hours at 50 DEG C.After addition 1M aqueous hydrochloric acid solution makes it be in acid into reaction mixture, chlorine is used Imitative and methanol mixed extractant solvent water layer, organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure, obtains title compound Object (17mg).
MS (m/z): 370 [M+H]+
38 6- of reference example { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine -4- carboxylic acid
[process 1] 6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic The manufacture of pyridine -4- carboxylate methyl ester
To the chloro- 2- of 6- obtained in reference example 3 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester DIPEA (88 μ L), (1S) -1- cyclopropylethyI amine (16mg) are added in DMF (2mL) solution of (50mg), it is small that 3 are stirred at 80 DEG C When.With silica gel chromatography reaction mixture, title compound (40mg) is obtained.
MS (m/z): 344 [M+H]+
[process 2] 6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic The manufacture of pyridine -4- carboxylic acid
To 6- obtained in process 1 { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) THF (9mL) of pyrimidine -4- carboxylate methyl ester (40mg), lithium hydroxide monohydrate (10mg) is added in water (3mL) solution, It is stirred at room temperature 1 hour.After addition 1M aqueous hydrochloric acid solution makes it be in acid into reaction mixture, removes THF under reduced pressure, use chlorine Imitative aqueous layer extracted.Organic layer is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure, obtains title compound (36mg).
MS (m/z): 330 [M+H]+
39 6- of reference example { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine -4- carboxylic acid
According to the method for 38 process 1,2 of reference example, (1S) -1- cyclopropyl second is replaced using (1R) -1- cyclopropylethyI amine Amine is synthesized, and title compound is obtained.
MS (m/z): 330 [M+H]+
40 6- of reference example { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid
According to the method for 38 process 1,2 of reference example, (2S) -3,3- dimethylbutane -2- amine is used to replace (1S) -1- ring Propylethylamine is synthesized, and title compound is obtained.
MS (m/z): 346 [M+H]+
41 6- of reference example { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid
According to the method for 38 process 1,2 of reference example, (2R) -3,3- dimethylbutane -2- amine is used to replace (1S) -1- ring Propylethylamine is synthesized, and title compound is obtained.
MS (m/z): 346 [M+H]+
42 6- of reference example { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carboxylic acid
According to the method for 38 process 1,2 of reference example, (1S, 2S) -2- (difluoro-methoxy) ring obtained in reference example 7 is used Amylamine hydrochloride replaces (1S) -1- cyclopropylethyI amine to be synthesized, and obtains title compound.
MS (m/z): 396 [M+H]+
43 6- of reference example { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine -4- carboxylate methyl ester
To 6- obtained in 38 process 1 of reference example { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester (820mg) DMF (8.0mL) solution in 60% sodium hydride is added at room temperature (115mg) is stirred 3 minutes.Then, iodomethane (1.4g) is added, stirs 5 minutes.Then, additional 60% sodium hydride (11mg), Stirring 5 minutes.After reaction solution is diluted with chloroform, water is added to carry out liquid separation, chloroform aqueous layer extracted is further used, by the organic of merging Layer is dry with anhydrous magnesium sulfate, is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (665mg)。
MS (m/z): 358 [M+H]+
44 6- of reference example { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid
According to the method for 38 process 1,2 of reference example, (1S) -1- is replaced using (1R) -1- (4- methoxyphenyl) ethamine CyclopropylethyI amine is synthesized, and title compound is obtained.
MS (m/z): 396 [M+H]+
45 6- of reference example { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid
[process 1] 6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester manufacture
To [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] benzyq carbamate obtained in 7 process 2 of reference example It is gradually added 60% sodium hydride (149mg), stirs 10 minutes on a small quantity at room temperature in DMF (5mL) solution of (710mg).Then, It is added iodomethane (530mg), stirs 2 hours.After reaction mixture is diluted with ethyl acetate, water is added to carry out liquid separation, further Water layer is extracted with ethyl acetate.Combined organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure.It is residue obtained to use silica gel Column chromatography purifying, obtains grease (338mg).20% hydrogen-oxygen is added into ethyl alcohol (6mL) solution of gained grease (300mg) Change palladium (being carried on active carbon, 100mg), pressure catalysis reduction in progress.4M hydrogen chloride-ethyl acetate solution (2mL), filtering is added After reaction solution is to remove palladium, mother liquor is concentrated under reduced pressure, obtains solids (271mg).To obtained solid object (75mg) and reference example 3 Obtained in the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester (50mg) DMF (2mL) it is molten DIPEA (0.18mL) is added in liquid, is stirred 3 hours at 100 DEG C.With silica gel chromatography reaction mixture, title is obtained Compound (102mg).
MS (m/z): 424 [M+H]+
[process 2] 6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid manufacture
According to the method for 38 process 2 of reference example, { [(1S, 2S) -2- (difluoro-methoxy) ring of 6- obtained in process 1 is used Amyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester replaces 6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester carries out Synthesis, obtains title compound.
MS (m/z): 410 [M+H]+
46 6- of reference example { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine -4- carboxylic acid
[process 1] 6- { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carboxylate methyl ester manufacture
Into DMF (20mL) solution of N- [(1S, 2S) -2- hydroxycyclopent base] t-butyl carbamate (4.0g) ice-cold It is lower that 60% sodium hydride (870mg) is gradually added on a small quantity, it is stirred at room temperature 10 minutes.Then, in ice-cold lower addition iodomethane (3.1g), is stirred at room temperature.After reaction mixture is diluted with ethyl acetate, water is added to carry out liquid separation, further uses acetic acid second Ester aqueous layer extracted.It is dry with anhydrous sodium sulfate after organic layer with the merging of saturated common salt water washing, it is concentrated under reduced pressure.Gained Residue silica gel chromatography obtains solids 1 (2.3g).Add into methylene chloride (10mL) solution of obtained solid object 1 Enter 4M hydrogen chloride-ethyl acetate solution (5.3mL), is stirred at room temperature 4 hours.Solvent under reduced pressure is concentrated, solids 2 is obtained (1.5g).To (pyrazolo [5,1-b] [1,3] thiazole -7- of the chloro- 2- of 6- obtained in obtained solid object 2 (93mg) and reference example 3 Base) pyrimidine -4- carboxylate methyl ester (150mg) DMF (2.0mL) solution in DIPEA (0.26mL) is added, stirred at 100 DEG C 3 small When.With silica gel chromatography reaction mixture, title compound (112mg) is obtained.
MS (m/z): 374 [M+H]+
[process 2] 6- { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carboxylic acid manufacture
According to the method for 38 process 2 of reference example, use 6- obtained in process 1 { [(1S, 2S) -2- methoxy cyclopentyl] Amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester replaces 6- { [(1S) -1- cyclopropyl second Base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester synthesized, obtain title compound Object.
MS (m/z): 360 [M+H]+
47 6- of reference example { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid
[process 1] 6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester manufacture
To the chloro- 5- methyl -2- of 6- obtained in reference example 5 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic (2S) -3,3- dimethylbutane -2- amine (33mg) and DIPEA (56 μ L) are added in NMP (1mL) solution of sour methyl esters (50mg), It is stirred 30 minutes 2 hours at 110 DEG C.After being diluted with ethyl acetate, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, into one Water layer is extracted with ethyl acetate in step, and combined organic layer is dry with anhydrous magnesium sulfate, is concentrated under reduced pressure.It is residue obtained to use silicon Rubber column gel column chromatogram purification obtains title compound (39mg).
MS (m/z): 374 [M+H]+
[process 2] 6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine -4- carboxylic acid manufacture
To 6- obtained in process 1 { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) THF (5.0mL) of pyrimidine -4- carboxylate methyl ester (35mg), hydrogen-oxygen is added in water (2.0mL) solution Change lithium monohydrate (12mg), is stirred 1 hour at 50 DEG C.1M aqueous hydrochloric acid solution is added into reaction mixture makes it in acidity Afterwards, with the mixed extractant solvent water layer of chloroform and methanol.Organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure, is obtained Title compound (35mg).
MS (m/z): 360 [M+H]+
48 6- of reference example { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid
According to 47 process 1 of reference example, the method for process 2, (2S) -3,3- bis- is replaced using (1S) -1- cyclopropylethyI amine Methybutane -2- amine is synthesized, and title compound is obtained.
MS (m/z): 344 [M+H]+
49 6- of reference example [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine -4- carboxylic acid
According to the method for 38 process 1,2 of reference example, (1S) -1- cyclopropyl is replaced using 2,2- dimethylpropane -1- amine Ethamine is synthesized, and title compound is obtained.
MS (m/z): 332 [M+H]+
50 1- cyclopropyl -3- piperidin-4-yl urea hydrochloride of reference example
TEA (0.5mL) and diphenyl phosphate azide are added into toluene (3mL) solution of cyclopropane-carboxylic acid (300mg) (1.1g) is stirred 3 hours at 80 DEG C.Then, 4- amino piperidine -1- carboxylic acid tert-butyl ester (600mg) is added at room temperature, stirring 1 hour.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain solids (234mg).It is solid to gained 4M hydrogen chloride-ethyl acetate solution (0.6mL) is added in methylene chloride (5mL) solution of body object (230mg), is stirred at room temperature Overnight.Reaction solution is concentrated under reduced pressure, title compound (200mg) is obtained.
MS (m/z): 184 [M-Cl]+
The fluoro- 2- methylpropane -2- base ester of 51 piperidin-4-yl carbamic acid 1- of reference example
To 1- benzyl piepridine -4- amine (4.0g) and iodate 1- { [(the fluoro- 2- methylpropane -2- base of 1-) oxygroup] carbonyl } -3- Methyl-1 H- imidazoles -3-(7.6g) (such as according to Bioorganic Medicinal Chemistry, 2011,19,1580- Recorded in 1593. method synthesis) acetonitrile (20mL) solution in be added TEA (5.9mL), be stirred at room temperature 1 hour.To anti- It answers and water is added in mixture, extracted with chloroform.Organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure, residue obtained use Silica gel chromatography obtains solids (2.0g).20% is added into ethyl alcohol (20mL) solution of obtained solid object (2.0g) Palladium dydroxide (is carried on active carbon, 1.0g), pressure catalysis reduction in progress.After filtering reacting liquid is to remove palladium, mother liquor is depressurized Concentration, it is residue obtained to be washed with ethyl acetate, obtain title compound (306mg).
MS (m/z): 219 [M+H]+
Reference example 52 piperidin-4-yl carbamic acid 2- (dimethylamino) ethyl ester
According to the method for 25 process 1 of reference example, 2,2- difluoroethanol is replaced to be closed using 2-dimethylaminoethanol At obtaining title compound.
1H-NMR (CDCl3) δ: 1.21-1.35 (2H, m), 1.90-2.00 (2H, m), 2.28 (6H, s), 2.51- 2.59 (2H, m), 2.62-2.70 (2H, m), 3.00-3.10 (2H, m), 3.52-3.64 (1H, m), 4.14 (2H, t), 4.74 (1H, br)
Embodiment 1N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide hydrochloride
[process 1] N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide manufacture
To 6- obtained in reference example 38 { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid (15mg) DMF (1.0mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxamide (11mg), DIPEA (24 μ L), HATU (26mg), are stirred at room temperature 1 hour.With silica gel chromatography reaction mixture, obtain To title compound (9mg).
MS (m/z): 480 [M+H]+
[process 2] N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide hydrochloride manufacture
To N- obtained in process 1 (1- [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide (540mg) dichloromethane solution in be added 4M hydrogen chloride-ethyl acetate solution (0.5mL).Reaction solution is concentrated under reduced pressure, title compound (580mg) is obtained.
MS (m/z): 480 [M-Cl]+
Specific rotatory power [α]D 25=-45.2 (c=1.00, DMSO)
Embodiment 2N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide
According to the method for 1 process 1 of embodiment, N- (piperidin-4-yl) cyclopropyl is replaced using N- (4- piperidyl) acetamide Alkane carboxylic acid amides, obtains title compound.
MS (m/z): 454 [M+H]+
Embodiment 3N- (1- [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 40 { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (15mg) DMF (1.0mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxylic acid acyl Amine (11mg), DIPEA (23 μ L), HATU (25mg), are stirred at room temperature 1 hour.With silica gel chromatography reaction mixture, Obtain title compound (7mg).
MS (m/z): 496 [M+H]+
Embodiment 4N- (1- [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide
According to the method for embodiment 3, N- (piperidin-4-yl) cyclopropane carboxylic acid acyl is replaced using N- (4- piperidyl) acetamide Amine obtains title compound.
MS (m/z): 470 [M+H]+
Embodiment 5N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 45 { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrrole Azoles simultaneously [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (15mg) DMF (1.0mL) solution in N- (piperidines -4- is added Base) cyclopropane carboxamide (9.0mg), DIPEA (19 μ L), HATU (21mg), it is stirred at room temperature 3 hours.Use silica gel column chromatography Reaction mixture is purified, title compound (16mg) is obtained.
MS (m/z): 560 [M+H]+
Embodiment 6N- (1- [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide
To 6- obtained in reference example 47 { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (15mg) and N- (4- piperidyl) acetamide (9.0mg) DMF DIPEA (14 μ L), HATU (24mg) are added in (1.0mL) solution, is stirred at room temperature 30 minutes 1 hour.Use silica gel column chromatography Reaction mixture is purified, title compound (15mg) is obtained.
MS (m/z): 484 [M+H]+
Embodiment 7N- (1- [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 6, N- (4- piperidyl) acetyl is replaced using N- (piperidin-4-yl) cyclopropane carboxamide Amine obtains title compound.
MS (m/z): 510 [M+H]+
Embodiment 8N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclopropyl } methyl) amino] -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
To the chloro- 2- of 6- obtained in reference example 3 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester { 1- [(difluoro-methoxy) methyl] cyclopropyl } methylamine obtained in reference example 8 is added in DMF (1.5mL) solution of (200mg) (113mg) and DIPEA (236 μ L) are stirred 30 minutes 1 hour at 80 DEG C.Water is added into reaction solution, is extracted with ethyl acetate It takes, it is dry with anhydrous magnesium sulfate after saturated common salt water washing organic layer, it is concentrated under reduced pressure.It is residue obtained to use silicagel column color Spectrum purifying, obtains solids 1 (233mg).Add in the THF (4.0mL), water (1.0mL) solution of obtained solid object 1 (210mg) Enter lithium hydroxide monohydrate (32mg), is stirred 20 minutes at 40 DEG C.Reaction solution 1M aqueous hydrochloric acid solution is neutralized, is carried out It is concentrated under reduced pressure, obtains solids 2 (246mg).N- (piperidines-is added into DMF (0.5mL) solution of obtained solid object 2 (40mg) 4- yl) cyclopropane carboxamide (26mg), DIPEA (35 μ L), HATU (58mg), it is stirred at room temperature overnight.Add into reaction solution Enter water, is extracted with ethyl acetate.It is dry with anhydrous magnesium sulfate after saturated common salt water washing organic layer, it is concentrated under reduced pressure.Institute Residue silica gel chromatography is obtained, title compound (25mg) is obtained.
MS (m/z): 546 [M+H]+
Embodiment 9N- [1- ({ 6- [({ 1- [difluoromethoxy ylmethyl] cyclobutyl } methyl) amino] -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for embodiment 8, { 1- [(difluoro-methoxy) methyl] cyclobutyl } methylamine obtained in reference example 9 is used It replaces { 1- [(difluoro-methoxy) methyl] cyclopropyl } methylamine, obtains title compound.
MS (m/z): 560 [M+H]+
Embodiment 10N- [1- (6- [{ 1- [(difluoro-methoxy) methyl] cyclopenta } methylamino] -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for embodiment 8, { 1- [(difluoro-methoxy) methyl] cyclopenta } first obtained in reference example 10 is used Amine replaces { 1- [(difluoro-methoxy) methyl] cyclopropyl } methylamine, obtains title compound.
MS (m/z): 574 [M+H]+
Embodiment 11N- [1- ({ 6- [({ 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrans -4- base } methyl) amino] - 2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for embodiment 8, { 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrrole obtained in reference example 11 is used Mutter -4- base methylamine replaces { 1- [(difluoro-methoxy) methyl] cyclopropyl } methylamine, obtain title compound.
MS (m/z): 590 [M+H]+
Embodiment 12N- (1- [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 48 { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (20mg) DMF (1mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxamide (15mg), DIPEA (20 μ L), HATU (33mg), are stirred at room temperature 1 hour.With silica gel chromatography reaction mixture, obtain To title compound (21mg).
MS (m/z): 494 [M+H]+
Embodiment 13N- (1- [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide
According to the method for embodiment 12, N- (piperidin-4-yl) cyclopropane carboxylic acid is replaced using N- (4- piperidyl) acetamide Amide obtains title compound.
MS (m/z): 468 [M+H]+
Embodiment 14N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 42 { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (20mg) DMF (1mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxylic acid Amide (13mg), DIPEA (26 μ L), HATU (29mg), are stirred at room temperature 1 hour.It is reacted and is mixed with silica gel chromatography Object obtains title compound (7mg).
MS (m/z): 546 [M+H]+
Embodiment 15N- [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
To the chloro- 2- of 6- obtained in reference example 3 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester 2,2- dimethylpropane -1- amine (9.0mg) and DIPEA (50 μ L) are added in DMF (0.1mL) solution of (30mg), at 100 DEG C Stirring 3 hours.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain solids 1 (28mg).To institute Obtain the two of solids 1 (28mg)Lithium hydroxide monohydrate (7mg) is added in alkane (5.0mL), water (1.0mL) solution, 50 It is stirred 1 hour at DEG C.It is neutralized with 2M aqueous hydrochloric acid solution, reaction solution is concentrated under reduced pressure, solids 2 is obtained.To obtained solid object 2 DMF (1.5mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxamide, DIPEA (0.2mL), HATU (62mg), in room Temperature lower stirring 3 hours.Reaction mixture is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain title compound (27mg)。
MS (m/z): 482 [M+H]+
Embodiment 16N- (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
Under an argon to (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- of N- obtained in reference example 15 Base) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide (550mg) the tert-butyl alcohol (20mL) solution in TEA is added (534 μ L), (2R) -3,3- dimethylbutane -2- amine (258mg), are stirred overnight at 90 DEG C.Reaction mixture is depressurized dense Contracting, it is residue obtained to use silica gel chromatography, obtain title compound (570mg).
MS (m/z): 496 [M+H]+
Specific rotatory power [α]D 25=+14.0 (c=1.00, DMSO)
Embodiment 17N- (1- { [6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 37 { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (20mg) DMF (0.5mL) solution in be added N- (piperidin-4-yl) cyclopropane Carboxylic acid amides (11mg), DIPEA (10 μ L), HATU (40mg), are stirred at room temperature 3 hours.Reaction mixture is concentrated under reduced pressure, institute Residue silica gel chromatography is obtained, title compound (13mg) is obtained.
MS (m/z): 520 [M+H]+
Embodiment 18N- (1- [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) two Fluorakil 100 of -2,2-
According to the method for embodiment 12, the fluoro- N- of 2,2- bis- (4- piperidyl) acetyl obtained in 28 process 1 of reference example is used Amine replaces N- (piperidin-4-yl) cyclopropane carboxamide, obtains title compound.
MS (m/z): 504 [M+H]+
Embodiment 19N- (1- { [6- { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 46 { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (20mg) DMF (1mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxamide (14mg), DIPEA (29 μ L), HATU (32mg), are stirred at room temperature 30 minutes.With silica gel chromatography reaction mixture, Obtain title compound (13mg).
MS (m/z): 510 [M+H]+
[6- { [(1S) -1- cyclopropylethyl] the amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 20 Pyrimidine-4-yl] (4- hydroxy piperidine -1- base) methanone hvdrochloric acid salt
To 6- obtained in reference example 38 { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid (420mg) DMF (5mL) solution in be added piperidines -4- alcohol (194mg), DIPEA (662 μ L), HATU (727mg) is stirred at room temperature 1 hour.With silica gel chromatography reaction mixture, solids (530mg) is obtained.To 4M hydrogen chloride-ethyl acetate solution (0.6mL) is added in the ethyl acetate solution of obtained solid object.Reaction solution is depressurized dense Contracting, obtains title compound (560mg).
MS (m/z): 413 [M-Cl]+
Elemental analysis value is (with C19H24N6O2S·HCl+0.3H2O+0.2CH3CO2C2H5Meter)
Calculated value (%) C:52.93, H:5.81, N17.81
Measured value (%) C:52.68, H:5.78, N17.78
21 1- of embodiment { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) the fluoro- 2- methylpropane -2- base ester hydrochloride of carbamic acid 1-
According to the method for embodiment 20, the fluoro- 2- methyl-prop of piperidin-4-yl carbamic acid 1- obtained in reference example 51 is used Alkane -2- base ester replaces piperidines -4- alcohol, obtains title compound.
MS (m/z): 530 [M-Cl]+
(1- { [6- { [(the 2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 22 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for embodiment 3, carry out generation using piperidin-4-yl methyl carbamate obtained in 14 process 1 of reference example For N- (piperidin-4-yl) cyclopropane carboxamide, title compound is obtained.
MS (m/z): 486 [M+H]+
[6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 23 Azoles -7- base) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) ketone
According to the method for embodiment 3, N- (piperidin-4-yl) cyclopropane carboxamide is replaced using piperidines -4- alcohol, is marked Inscribe compound.
MS (m/z): 429 [M+H]+
(1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 24 Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate hydrochloride
[process 1] (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate manufacture
Under an argon to (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) obtained in reference example 14 Pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate (20mg) DMF (1mL) solution in be added DIPEA (16 μ L), (2R) -3- methybutane -2- amine (6mg) stirs 30 minutes 3 hours at 100 DEG C.After reaction solution is diluted with ethyl acetate, Saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, water layer is further extracted with ethyl acetate.Use saturated sodium bicarbonate aqueous solution It is dry with anhydrous magnesium sulfate after washing combined organic layer, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, it obtains To title compound (19mg).
MS (m/z): 472 [M+H]+
[process 2] (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate hydrochloride manufacture
To (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] obtained in process 1 [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate (56mg) ethyl acetate solution in plus Enter 4M hydrogen chloride-ethyl acetate solution (0.1mL).Reaction solution is concentrated under reduced pressure, with diethyl ether wash it is residue obtained after, carry out It is dry, obtain title compound (50mg).
MS (m/z): 472 [M-Cl]+
Elemental analysis value is (with C22H29N7O3S·HCl+1.0H2O meter)
Calculated value (%) C:50.23, H:6.13, N18.64
Measured value (%) C:50.47, H:6.08, N18.52
(1- { [6- { [(2S) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 25 Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate hydrochloride
According to the method for 24 process 1,2 of embodiment, (2R) -3- methyl fourth is replaced using (2S) -3- methybutane -2- amine Alkane -2- amine, obtains title compound.
MS (m/z): 472 [M-Cl]+
Elemental analysis value is (with C22H29N7O3S·HCl+H2O meter)
Calculated value (%) C:50.23, H:6.13, N18.64
Measured value (%) C:50.50, H:6.10, N18.27
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 26 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- is replaced using (1S) -1- cyclopropylethyI amine Amine obtains title compound.
MS (m/z): 470 [M+H]+
Specific rotatory power [α]D 25=-53.0 (c=1.00, DMSO)
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 27 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate hydrochloride
To (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] obtained in embodiment 26 [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate (2.26g) ethyl acetate (100mL) 4M hydrogen chloride-ethyl acetate solution (2.4mL) is added in solution.Reaction solution is concentrated under reduced pressure, title compound is obtained (2.35g)。
MS (m/z): 470 [M-Cl]+
Elemental analysis value is (with C22H27N7O3S·HCl+H2O meter)
Calculated value (%) C:50.42, H:5.77, N18.71
Measured value (%) C:50.53, H:5.66, N18.97
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 28 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes
According to the method for 1 process 1 of embodiment, using piperidin-4-yl urethanes (such as according to US1990/ The method synthesis recorded in 4918073) replace N- (piperidin-4-yl) cyclopropane carboxamide, obtain title compound.
MS (m/z): 484 [M+H]+
Specific rotatory power [α]D 25=-44.2 (c=1.00, DMSO)
(1- { [6- { [(the 2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 29 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 22 Carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester (200mg) DMF (3mL) solution in be added DIPEA (0.3mL), (2R) -3,3- dimethylbutane -2- amine (90mg) stirs 4 hours at 120 DEG C in tube sealing.By reaction solution ethyl acetate After dilution, liquid separation is carried out with saturated sodium bicarbonate aqueous solution, water layer is further extracted with ethyl acetate.Use saturated sodium bicarbonate water It is dry with anhydrous magnesium sulfate after solution washs combined organic layer, it is concentrated under reduced pressure.It is residue obtained pure with silica gel column chromatography Change, obtains title compound (160mg).
MS (m/z): 514 [M+H]+
Embodiment 30N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide
[process 1] (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl piperidin-4-yl) t-butyl carbamate manufacture
According to the method for 1 process 1 of embodiment, N- (piperidines -4- is replaced using N- (4- piperidyl) t-butyl carbamate Base) cyclopropane carboxamide, obtain title compound.
MS (m/z): 512 [M+H]+
[process 2] (4- amino piperidine -1- base) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone manufacture
To (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] obtained in process 1 Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) t-butyl carbamate (75mg) methylene chloride (2mL) solution in It is added TFA (0.5mL), is stirred at room temperature 1 hour.With silica gel chromatography reaction mixture, title compound is obtained (65mg)。
MS (m/z): 412 [M+H]+
[process 3] N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) benzamide manufacture
To (4- amino piperidine -1- base) obtained in process 2 [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazoles And [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone (20mg) methylene chloride (1mL) solution in be added DIPEA (25 μ L), chlorobenzoyl chloride (10mg), be stirred at room temperature 30 minutes.With silica gel chromatography reaction mixture, title compound is obtained Object (18mg).
MS (m/z): 516 [M+H]+
Embodiment 31N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) pyridine -3- carboxylic acid amides
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using pyridine -3- phosgene hydrochloride, is marked Inscribe compound.
MS (m/z): 517 [M+H]+
Embodiment 32N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) thiophene -2- carboxylic acid amides
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using thiophene -2- phosgene, obtains title compound Object.
MS (m/z): 522 [M+H]+
Embodiment 33N- (1- [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide hydrochloride
[process 1] N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide manufacture
To 6- obtained in reference example 43 { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) THF (3mL) of pyrimidine -4- carboxylate methyl ester (25mg), one water of lithium hydroxide is added in water (1mL) solution It closes object (9mg), is stirred at room temperature 30 minutes.Reaction solution is concentrated under reduced pressure, into DMF (2mL) solution of obtained solid object N- (piperidin-4-yl) cyclopropane carboxamide (18mg), DIPEA (74 μ L), HATU (40mg) is added, is stirred at room temperature 1 hour. After reaction solution is diluted with chloroform, water is added to carry out liquid separation, further uses chloroform aqueous layer extracted.Organic layer is done with anhydrous magnesium sulfate It is dry, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (30mg).
MS (m/z): 494 [M+H]+
[process 2] N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide hydrochloride manufacture
According to the method for embodiment 27, (the 1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) of the N- as obtained in process 1 Amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide obtains To title compound.
MS (m/z): 494 [M-Cl]+
Specific rotatory power [α]D 25=-35.7 (c=0.42, DMSO)
34 1- cyclopropyl -3- of embodiment (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urea
According to the method for 1 process 1 of embodiment, 1- cyclopropyl -3- piperidin-4-yl urea hydrochloric acid obtained in reference example 50 is used Salt replaces N- (piperidin-4-yl) cyclopropane carboxamide, obtains title compound.
MS (m/z): 495 [M+H]+
[6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole-of embodiment 35 7- yl) pyrimidine-4-yl] [4- (pyrimidine -2 --amino) piperidin-1-yl] ketone
To 6- obtained in reference example 43 { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) THF (10mL) of pyrimidine -4- carboxylate methyl ester (665mg), lithium hydroxide one is added in water (5mL) solution Hydrate (234mg) is stirred at room temperature 30 minutes.Reaction solution is concentrated under reduced pressure, to residue obtained middle addition 1M hydrochloric acid water After solution makes it be in acid, with the mixed extractant solvent water layer of chloroform and methanol.Organic layer is dry with anhydrous magnesium sulfate, it carries out It is concentrated under reduced pressure, obtains solids (600mg).N- (4- piperidyl) is added into DMF (1mL) solution of obtained solid object (15mg) Pyrimidine -2- amine (such as being synthesized according to the method recorded in WO2005/105779) (12mg), DIPEA (15 μ L), HATU (25mg) is stirred at room temperature 30 minutes 1 hour.With silica gel chromatography reaction mixture, title compound is obtained (14mg)。
MS (m/z): 504 [M+H]+
Embodiment 36N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) cyclopropane carboxamide
[process 1] 6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester Manufacture
To the chloro- 2- of 6- obtained in reference example 3 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylate methyl ester DIPEA (50 μ L), tert-butylamine (7mg) are added in DMF (0.5mL) solution of (30mg), is stirred 3 hours at 100 DEG C.It will reaction Solution is concentrated under reduced pressure, residue obtained to use silica gel chromatography, obtains title compound (15mg).
MS (m/z): 332 [M+H]+
[process 2] N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl piperidin-4-yl) cyclopropane carboxamide manufacture
To 6- obtained in process 1 (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Lithium hydroxide monohydrate (6mg) is added in the THF (5mL) of carboxylate methyl ester (15mg)-water (1mL) solution, stirs 1 at 40 DEG C Hour.It is neutralized with 2M aqueous hydrochloric acid solution, reaction solution is concentrated under reduced pressure, solids is obtained.To the DMF of obtained solid object N- (piperidin-4-yl) cyclopropane carboxamide (11mg), DIPEA (16 μ L), HATU (26mg) are added in (0.5mL) solution, in room Temperature lower stirring 3 hours.Reaction mixture is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain title compound (8mg)。
MS (m/z): 468 [M+H]+
Embodiment 37N- [1- ({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for 36 process 1,2 of embodiment, tert-butylamine is replaced using 1- methyl cyclopropyl amine hydrochlorate, obtains title Compound.
MS (m/z): 466 [M+H]+
Embodiment 38N- [1- (6- [(1- methoxyl group -2- methylpropane -2- base) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for 36 process 1,2 of embodiment, using 1- methoxyl group -2- methylpropane -2- amine hydrochlorate (such as according to The method synthesis recorded in WO2011/087837) tert-butylamine is replaced, obtain title compound.
MS (m/z): 498 [M+H]+
(1- { [6- { [(the 2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 39 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3,3- dimethylbutane -2- amine is used to replace (2R) -3- methyl Butane -2- amine, obtains title compound.
MS (m/z): 486 [M+H]+
(1- { [6- { [(the 2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 40 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes
To 6- obtained in reference example 41 { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (30mg) DMF (1mL) solution in be added piperidin-4-yl urethanes (example Such as synthesized according to the method recorded in US1990/4918073) (19mg), DIPEA (34mg), HATU (50mg), are stirred at room temperature It mixes 1 hour.After reaction mixture is diluted with ethyl acetate, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, further uses Ethyl acetate aqueous layer extracted.It is dry with anhydrous magnesium sulfate after washing the organic layer merged with saturated sodium bicarbonate aqueous solution, it carries out It is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (41mg).
MS (m/z): 500 [M+H]+
41 1- of embodiment { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester
According to the method for embodiment 29, (2R) -3,3- dimethylbutane -2- is replaced using (1S) -1- cyclopropylethyI amine Amine obtains title compound.
MS (m/z): 498 [M+H]+
Specific rotatory power [α]D 25=-35.4 (c=0.74, DMSO)
Embodiment 42N- (1- [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide
[process 1] (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) t-butyl carbamate manufacture
According to the method for embodiment 35, replace N- (4- piperidyl) phonetic using N- (4- piperidyl) t-butyl carbamate Pyridine -2- amine, obtains title compound.
MS (m/z): 526 [M+H]+
[process 2] (4- amino piperidine -1- base) [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone manufacture
To (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1- obtained in process 1 B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) t-butyl carbamate (150mg) methylene chloride TFA (1mL) is added in (2mL) solution, is stirred at room temperature 30 minutes.With silica gel chromatography reaction mixture, marked It inscribes compound (117mg).
MS (m/z): 426 [M+H]+
[process 3] N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) benzamide manufacture
To (4- amino piperidine -1- base) obtained in process 2 [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone (20mg) methylene chloride (1mL) solution in be added DIPEA (24 μ L), chlorobenzoyl chloride (10mg), are stirred at room temperature 30 minutes.With silica gel chromatography reaction mixture, obtain Title compound (13mg).
MS (m/z): 530 [M+H]+
Embodiment 43N- (1- { [6- (cyclo propyl methoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 15 Base] carbonyl piperidin-4-yl) cyclopropane carboxamide (20mg) and cyclopropyl-carbinol (33mg) THF (3.0mL) solution in ice 60% sodium hydride of cold lower addition (2mg) stirs 1 hour at 70 DEG C.After reaction solution is diluted with ethyl acetate, water is added to be divided Water layer is further extracted with ethyl acetate in liquid.It is dry with anhydrous sodium sulfate after organic layer with the merging of saturated common salt water washing, It is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (15mg).
MS (m/z): 467 [M+H]+
Embodiment 44N- [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for embodiment 43, cyclopropyl-carbinol is replaced using 3,3- dimethylbutane -2- alcohol, is obtained titled Close object.
MS (m/z): 497 [M+H]+
Embodiment 45N- (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] Carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 43, cyclopropyl-carbinol is replaced using cyclobutanol, obtains title compound.
MS (m/z): 467 [M+H]+
Embodiment 46N- (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- is replaced using (1R) -1- cyclopropylethyI amine Amine obtains title compound.
MS (m/z): 480 [M+H]+
Embodiment 47N- (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide hydrochloride
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 15 Base] carbonyl piperidin-4-yl) cyclopropane carboxamide (50mg) DMF (1mL) solution in be added DIPEA (60 μ L), (1R) -1- ring Propylethylamine (12mg) stirs 40 minutes 1 hour at 70 DEG C.Then, (1R) -1- cyclopropylethyI amine (11mg) is added, 70 It is stirred 4 hours at DEG C.After reaction solution is diluted with ethyl acetate, adds water to carry out liquid separation, water layer is further extracted with ethyl acetate. Combined organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain solid Object (50mg).4M hydrogen chloride-ethyl acetate solution (52 μ L) is added into the ethyl acetate solution of obtained solid object.It will react molten Liquid is concentrated under reduced pressure, and is washed with diethyl ether residue obtained, obtains title compound (35mg).
MS (m/z): 481 [M-Cl]+
Embodiment 48N- [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 15 Base] carbonyl piperidin-4-yl) cyclopropane carboxamide (20mg) NMP (1mL) solution in be added DIPEA (16 μ L), 2- amino -2- Methylpropane -1- alcohol (6mg) stirs 2 hours at 100 DEG C.Additional 2- amino-2-methyl propane -1- alcohol (6mg), at 110 DEG C Lower stirring 2 hours.With silica gel chromatography reaction mixture, title compound (8mg) is obtained.
MS (m/z): 484 [M+H]+
[6- { [(1S) -1- cyclopropylethyl] the amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 49 Pyrimidine-4-yl] [4- (1,2- Azoles -3- base amino) piperidin-1-yl] ketone
Under an argon to 4- oxo-piperidine -1- carboxylic acid tert-butyl ester (250mg) and differentThe methanol of azoles -3- amine (106mg) Acetic acid (75mg) and borine -2- picoline complex compound (134mg) are added in (5mL) solution, is stirred at room temperature 3 hours.To Saturated sodium bicarbonate aqueous solution is added in reaction mixture, is extracted with ethyl acetate.Organic layer is dry with anhydrous magnesium sulfate, into Row is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain grease (109mg).Gained grease is dissolved in 2M chlorine Change hydrogen-methanol solution (5mL), is stirred at room temperature overnight.Reaction mixture is concentrated under reduced pressure, is washed with diethyl ether residue obtained Afterwards, it is dried, obtains solids (90mg).To 6- { [(1S) -1- ring obtained in obtained solid object (9mg) and reference example 38 Ethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (10mg) DMF (1mL) solution Middle addition DIPEA (11 μ L), HATU (17mg), are stirred at room temperature 30 minutes 1 hour.Reaction mixture is concentrated under reduced pressure, institute Residue silica gel chromatography is obtained, title compound (14mg) is obtained.
MS (m/z): 479 [M+H]+
[6- { [(1S) -1- cyclopropylethyl] the amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 50 Pyrimidine-4-yl] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone
According to the method for embodiment 49, replaced using thiazole -2- amine differentAzoles -3- amine, obtains title compound.
MS (m/z): 495 [M+H]+
[6- { [(1S) -1- cyclopropylethyl] the amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 51 Pyrimidine-4-yl] { 4- [(3- methyl-1,2- Azoles -5- base) amino] piperidin-1-yl } firstKetone
It is different using 3- methyl according to the method for embodiment 49Azoles -5- amine is different to replaceAzoles -3- amine, obtains titled Close object.
MS (m/z): 493 [M+H]+
Embodiment 52N- (1- { [6- { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To 6- obtained in reference example 44 { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine -4- carboxylic acid (20mg) DMF (1mL) solution in be added N- (piperidin-4-yl) cyclopropane carboxylic acid acyl Amine (12mg), DIPEA (26 μ L), HATU (29mg), are stirred at room temperature 1 hour.With silica gel chromatography reaction mixture, Obtain title compound (16mg).
MS (m/z): 546 [M+H]+
Embodiment 53 (1- [6- { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for embodiment 52, carry out generation using piperidin-4-yl methyl carbamate obtained in 14 process 1 of reference example For N- (piperidin-4-yl) cyclopropane carboxamide, title compound is obtained.
MS (m/z): 536 [M+H]+
Embodiment 54N- (1- { [6- { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide
According to the method for embodiment 52, N- (piperidin-4-yl) cyclopropane is replaced using N- (4- piperidyl) benzamide Carboxylic acid amides obtains title compound.
MS (m/z): 582 [M+H]+
Embodiment 55N- (1- [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 48, (2S) -2- amino -3,3- dimethylbutane -1- alcohol is used to replace 2- amino -2- Methylpropane -1- alcohol, obtains title compound.
MS (m/z): 512 [M+H]+
Embodiment 56 (4- hydroxy piperidine -1- base) [6- { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazoles And [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone
According to the method for embodiment 52, N- (piperidin-4-yl) cyclopropane carboxamide is replaced using piperidines -4- alcohol, is obtained Title compound.
MS (m/z): 479 [M+H]+
Embodiment 57 (1- [6- { [(1R) -1- (4- methoxyphenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) the fluoro- 2- methylpropane -2- base ester of carbamic acid 1-
According to the method for embodiment 52, the fluoro- 2- methyl-prop of piperidin-4-yl carbamic acid 1- obtained in reference example 51 is used Alkane -2- base ester replaces N- (piperidin-4-yl) cyclopropane carboxamide, obtains title compound.
MS (m/z): 596 [M+H]+
Embodiment 58 [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- Hydroxy piperidine -1- base) ketone
To [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- obtained in reference example 29 Hydroxy piperidine -1- base) ketone (2.2g) the tert-butyl alcohol (10mL) solution in be added tert-butylamine (1.3g), in tube sealing, at 130 DEG C Lower stirring 10 hours.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain title compound (2.1g)。
MS (m/z): 401 [M+H]+
(the 1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] of embodiment 59 Carbonyl } piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using tert-butylamine, obtains title Compound.
MS (m/z): 458 [M+H]+
(the 1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] of embodiment 60 Carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester
According to the method for embodiment 29, (2R) -3,3- dimethylbutane -2- amine is replaced using tert-butylamine, obtains title Compound.
MS (m/z): 486 [M+H]+
[1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 61 Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methyl fourth is replaced using 2- amino-2-methyl propane -1- alcohol Alkane -2- amine, obtains title compound.
MS (m/z): 474 [M+H]+
[6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 62 Azoles -7- base) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) methanone hvdrochloric acid salt
[process 1] [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) ketone manufacture
To [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- obtained in reference example 29 Hydroxy piperidine -1- base) ketone (5g) 2- propyl alcohol (50mL) solution in be added DIPEA (9.5mL), (2R) -3,3- dimethyl butyrate Alkane -2- amine (2.8g), is stirred overnight at 100 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, Obtain title compound (6.0g).
MS (m/z): 429 [M+H]+
[process 2] [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) methanone hvdrochloric acid salt manufacture
According to the method for embodiment 27, [6- { [(2R) -3,3- dimethylbutane -2- base] ammonia as obtained in process 1 Base } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- hydroxy piperidine -1- base) ketone obtain it is titled Close object.
MS (m/z): 429 [M-Cl]+
Elemental analysis value is (with C21H28N6O2S·HCl+0.5H2O meter)
Calculated value (%) C:52.22, H:6.14, N18.27
Measured value (%) C:52.09, H:6.06, N18.26
(1- { [6- { [(the 2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1- of embodiment 63 B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2S) -2- amino -3,3- dimethylbutane -1- alcohol is used to replace (2R) -3- methybutane -2- amine, obtains title compound.
MS (m/z): 502 [M+H]+
[1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole-of embodiment 64 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 14 Carbonyl } piperidin-4-yl) methyl carbamate (25mg) and 3,3- dimethylbutane -2- alcohol (61mg) THF (2mL) solution in In 60% sodium hydride of ice-cold lower addition (4mg), it is stirred at room temperature overnight.After reaction solution is diluted with ethyl acetate, add water into Row liquid separation, is further extracted with ethyl acetate water layer.Combined organic layer is dry with anhydrous sodium sulfate, it is concentrated under reduced pressure. It is residue obtained to use silica gel chromatography, obtain title compound (6mg).
MS (m/z): 487 [M+H]+
(1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl of embodiment 65 Base } piperidin-4-yl) methyl carbamate
According to the method for embodiment 64,3,3- dimethylbutane -2- alcohol is replaced using cyclobutanol, obtains title compound Object.
MS (m/z): 457 [M+H]+
Embodiment 66N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) Methanesulfomide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using mesyl chloride, obtains title compound.
MS (m/z): 490 [M+H]+
Embodiment 67N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropyl-sulfonylamide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using cyclopropyl sulfonic acid chloride, obtains title compound.
MS (m/z): 516 [M+H]+
Embodiment 68N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) ethyl sulfonamide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using ethyl sulfonic chloride, obtains title compound.
MS (m/z): 504 [M+H]+
Embodiment 69N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) -2- methyl propanamide
To 6- (tert-butylamino) -2- obtained in 36 process 1 of embodiment (pyrazolo [5,1-b] [1,3] thiazole -7- base) The 1,4- bis- of pyrimidine -4- carboxylate methyl ester (280mg)2M sodium hydrate aqueous solution (1.27mL) is added in alkane (3mL) solution, It is stirred 1 hour at 50 DEG C.It is neutralized with 2M aqueous hydrochloric acid solution, reaction solution is concentrated under reduced pressure, solid content (50mg) is obtained.To gained In DMF (0.3mL) solution of solids be added DIPEA (41mg), 2- methyl-N- (4- piperidyl) propionamide (such as according to The method recorded in Bioorganic and Medicinal Chemistry Letters, 2012,22,3157-3162. is closed At) (52mg), HATU (87mg), it is stirred at room temperature 1 hour.Reaction mixture is concentrated under reduced pressure, after being diluted with chloroform, uses silicon Rubber column gel column chromatogram purification obtains title compound (28mg).
MS (m/z): 470 [M+H]+
Embodiment 70N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) two Fluorakil 100 of -2,2-
According to the method for embodiment 69, the fluoro- N- of 2,2- bis- (4- piperidyl) acetyl obtained in 28 process 1 of reference example is used Amine replaces 2- methyl-N- (4- piperidyl) propionamide, obtains title compound.
MS (m/z): 478 [M+H]+
(the 1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] of embodiment 71 Carbonyl } piperidin-4-yl) urethanes
According to the method for embodiment 69, using piperidin-4-yl urethanes (such as according in US19904918073 The method of record synthesizes) replace 2- methyl-N- (4- piperidyl) propionamide to be synthesized, obtain title compound.
MS (m/z): 472 [M+H]+
Embodiment 72 [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyridine -2- base amino) piperidin-1-yl] ketone
To [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- obtained in reference example 18 (pyridine -2- base amino) piperidin-1-yl] ketone (25mg) NMP (0.5mL) solution in be added DIPEA (20 μ L), tert-butylamine (8mg) is stirred 2 hours at 120 DEG C.Additional tert-butylamine (8mg), is stirred for 1 hour at 120 DEG C.It is pure with silica gel column chromatography Change reaction mixture, obtains title compound (8mg).
MS (m/z): 477 [M+H]+
(1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 73 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes
To 6- obtained in reference example 39 { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carboxylic acid (50mg) DMF (0.3mL) solution in be added piperidin-4-yl urethanes (such as according to The method synthesis recorded in US1990/4918073) (52mg), DIPEA (59mg), HATU (87mg), it is small to be stirred at room temperature 3 When.Reaction mixture is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain title compound (30mg).
MS (m/z): 484 [M+H]+
(1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 74 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethane ester hydrochloride
According to embodiment 27, (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrrole as obtained in embodiment 73 Azoles simultaneously [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes obtains title compound Object.
MS (m/z): 484 [M-Cl]+
Elemental analysis value is (with C23H29N7O3S·HCl+1.1H2O meter)
Calculated value (%) C:51.17, H:6.01, N18.16
Measured value (%) C:50.92, H:6.12, N17.95
Embodiment 75 [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone
According to the method for embodiment 72, [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiophene obtained in reference example 19 is used Azoles -7- base) pyrimidine-4-yl] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone replaces the [chloro- 2- (pyrazolo of 6- [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyridine -2- base amino) piperidin-1-yl] ketone, obtain title compound Object.
MS (m/z): 483 [M+H]+
Embodiment 76 [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyrimidine -2 --amino) piperidin-1-yl] ketone
According to the method for embodiment 72, [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiophene obtained in reference example 20 is used Azoles-7- base) pyrimidine-4-yl] [4- (pyrimidine -2 --amino) piperidin-1-yl] ketone replaces [the chloro- 2- of 6- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyridine -2- base amino) piperidin-1-yl] ketone, obtain title compound.
MS (m/z): 478 [M+H]+
(1- { [6- { [(1R) -1- (4- fluorophenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 77 Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
Under an argon to (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) obtained in reference example 14 Pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate (20mg) DMF (1mL) solution in be added DIPEA (25 μ L), (1R) -1- (4- fluorophenyl) ethamine (18 μ L), is stirred 4 hours at 80 DEG C.After reaction solution is diluted with ethyl acetate, it is added full Liquid separation is carried out with sodium bicarbonate aqueous solution, water layer is further extracted with ethyl acetate.Conjunction is washed with saturated sodium bicarbonate aqueous solution And organic layer after, it is dry with anhydrous magnesium sulfate, be concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title Compound (24mg).
MS (m/z): 524 [M+H]+
Embodiment 78N- [1- ({ 6- [(azetidine -3- ylmethyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 15 Base] carbonyl piperidin-4-yl) cyclopropane carboxamide (30mg) DMF (1mL) solution in be added DIPEA (48 μ L), 3- (amino first Base) azetidine -1- carboxylic acid tert-butyl ester (19mg), is stirred 2 hours at 120 DEG C.After reaction solution is diluted with ethyl acetate, Saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, water layer is further extracted with ethyl acetate.Use saturated sodium bicarbonate aqueous solution It is dry with anhydrous magnesium sulfate after washing combined organic layer, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, it obtains To solids (40mg).TFA (1mL) is added into methylene chloride (1mL) solution of obtained solid object (35mg), stirs at room temperature It mixes 1 hour.With silica gel chromatography reaction mixture, title compound (29mg) is obtained.
MS (m/z): 481 [M+H]+
Embodiment 79N- (1- { [6- { [(1R) -1- (4- fluorophenyl) ethyl] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methyl propanamide
According to the method for embodiment 77, (1- { [the chloro- 2- of the 6- (pyrazolo [5,1-b] of N- obtained in reference example 16 is used [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methyl propanamide replaces (the 1- { [chloro- 2- (pyrazoles of 6- And [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate, obtain title compound.
MS (m/z): 536 [M+H]+
[1- ({ 6- [(2- methybutane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 80 Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- is replaced using 2- methybutane -2- amine Amine obtains title compound.
MS (m/z): 472 [M+H]+
Embodiment 81 (4- hydroxy piperidine -1- base) [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] methanone hvdrochloric acid salt
[process 1] (4- hydroxy piperidine -1- base) [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] ketone manufacture
To (4- { [tert-butyl (dimethyl) silylation] oxygroup } piperidin-1-yl) [the chloro- 2- of 6- obtained in reference example 30 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone (840mg) n-butyl alcohol (10mL) solution in be added DIPEA (1.2mL), pentane -3- amine (459mg) are stirred 4 hours at 80 DEG C.Reaction solution is concentrated under reduced pressure, residue obtained use Silica gel chromatography obtains solids (792mg).1M tetra- is added into THF (5mL) solution of obtained solid object (790mg) Butyl ammonium fluoride (THF solution, 6.0mL), is stirred at room temperature 3 hours.Saturated aqueous ammonium chloride is added into reaction solution, uses Chloroform extraction, organic layer is dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, it obtains Title compound (474mg).
MS (m/z): 415 [M+H]+
[process 2] (4- hydroxy piperidine -1- base) [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] methanone hvdrochloric acid salt manufacture
To (4- hydroxy piperidine -1- base) obtained in process 1 [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone (474mg) ethyl acetate (10mL) solution in be added 4M hydrogen chloride-acetic acid second Ester solution (0.57mL).Reaction solution is concentrated under reduced pressure, title compound (517mg) is obtained.
MS (m/z): 415 [M-Cl]+
Elemental analysis value is (with C20H26N6O2S·HCl+0.5H2O meter)
Calculated value (%) C:52.22, H:6.14, N18.27
Measured value (%) C:52.09, H:6.06, N18.26
(the 1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] of embodiment 82 Carbonyl } piperidin-4-yl) carbamic acid propyl ester
By (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 23 Carbonyl } piperidin-4-yl) carbamic acid propyl ester (30mg) is dissolved in NMP (0.5mL), DIPEA (17mg), tert-butylamine is added (14mg) is stirred 3 hours at 130 DEG C in tube sealing.Reaction solution is concentrated under reduced pressure, it is residue obtained pure with silica gel column chromatography Change, obtains title compound (25mg).
MS (m/z): 486 [M+H]+
(1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 83 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester
According to the method for embodiment 82, tert-butylamine is replaced using (1R) -1- cyclopropylethyI amine, obtains title compound.
MS (m/z): 498 [M+H]+
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 84 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester
According to the method for embodiment 82, tert-butylamine is replaced using (1S) -1- cyclopropylethyI amine, obtains title compound.
MS (m/z): 498 [M+H]+
(1- { [6- { [(the 2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 85 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester
According to the method for embodiment 82, uses (2R) -3,3- dimethylbutane -2- amine to replace tert-butylamine, obtain title Compound.
MS (m/z): 514 [M+H]+
(1- { [6- { [(the 2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 86 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester
According to the method for embodiment 82, uses (2S) -3,3- dimethylbutane -2- amine to replace tert-butylamine, obtain title Compound.
MS (m/z): 514 [M+H]+
[1- ({ 6- [(2,2- dimethyl propyl) the amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 87 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate hydrochloride
[process 1] [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] and methyl carbamate manufacture
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane-is replaced using 2,2- dimethylpropane -1- amine 2- amine, obtains title compound.
MS (m/z): 472 [M+H]+
[process 2] [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] and methyl carbamate hydrochloride manufacture
To [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene obtained in process 1 Azoles -7- base) pyrimidine-4-yl carbonyl) piperidin-4-yl] and methyl carbamate (48mg) ethyl acetate (3mL) solution in be added 4M hydrogen chloride-ethyl acetate solution (50 μ L).Reaction solution is concentrated under reduced pressure, it is dry, obtain title compound (51mg).
MS (m/z): 472 [M-Cl]+
Elemental analysis value is (with C22H29N7O3S·HCl+1.6H2O meter)
Calculated value (%) C:49.22, H:6.23, N18.26
Measured value (%) C:49.03, H:6.03, N18.35
(1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 88 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 24 Carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate (20mg) ethyl alcohol (1mL) solution in be added DIPEA (30 μ L), (1R) -1- cyclopropylethyI amine (14 μ L), is stirred overnight at 80 DEG C.With silica gel chromatography reaction mixture, title is obtained Compound (15mg).
MS (m/z): 514 [M+H]+
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 89 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate
According to the method for embodiment 88, (1R) -1- cyclopropylethyI amine is replaced using (1S) -1- cyclopropylethyI amine, is obtained Title compound.
MS (m/z): 514 [M+H]+
(1- { [6- { [(the 2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 90 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate
According to the method for embodiment 88, (2R) -3,3- dimethylbutane -2- amine is used to replace (1R) -1- cyclopropyl second Amine obtains title compound.
MS (m/z): 530 [M+H]+
(1- { [6- { [(the 2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 91 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate
According to the method for embodiment 88, (2S) -3,3- dimethylbutane -2- amine is used to replace (1R) -1- cyclopropyl second Amine obtains title compound.
MS (m/z): 530 [M+H]+
Embodiment 92N- (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 27 Base] carbonyl piperidin-4-yl) -2- methoxyl acetamide (50mg) 2- propyl alcohol (1mL) solution in be added DIPEA (60 μ L), (1R) -1- cyclopropylethyI amine (49mg) stirs 3 hours at 90 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silicagel column Chromatogram purification obtains title compound (42mg).
MS (m/z): 484 [M+H]+
Embodiment 93N- (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide
According to the method for embodiment 92, (2R) -3,3- dimethylbutane -2- amine is used to replace (1R) -1- cyclopropyl second Amine obtains title compound.
MS (m/z): 500 [M+H]+
{ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic for embodiment 94 Pyridine -4- base } (4- hydroxy piperidine -1- base) ketone
To 6- obtained in reference example 49 [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine -4- carboxylic acid (27mg) DMF (0.5mL) solution in be added piperidines -4- alcohol (16mg), DIPEA (28 μ L), HATU (62mg), is stirred at room temperature overnight.Then, HATU (15mg) is added, is stirred at room temperature 3 hours.It is pure with silica gel column chromatography Change reaction mixture, obtains title compound (16mg).
MS (m/z): 415 [M+H]+
Embodiment 95 [1- (6- [{ [1- (methoxy) cyclopropyl] methyl } (methyl) amino] -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for 24 process 1 of embodiment, 1- obtained in reference example 13 (1- (methoxy) cyclopropyl)-is used N- methyl methylamine hydrochloride replaces (2R) -3- methybutane -2- amine, obtains title compound.
MS (m/z): 514 [M+H]+
(1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 96 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro carbethoxy hydrochloride
[process 1] (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester manufacture
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 25 Carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester (20mg) ethyl alcohol (1mL) solution in be added DIPEA (29 μ L), (1R) -1- cyclopropylethyI amine (14 μ L), is stirred overnight at 80 DEG C.With silica gel chromatography reaction mixture, title is obtained Compound (14mg).
MS (m/z): 520 [M+H]+
[process 2] (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl piperidin-4-yl) carbamic acid 2,2- difluoro carbethoxy hydrochloride manufacture
To (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] obtained in process 1 Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester (490mg) ethyl acetate solution Middle addition 4M hydrogen chloride-ethyl acetate solution (0.47mL).Reaction solution is concentrated under reduced pressure, is washed with diethyl ether residue obtained Afterwards, it is dried, obtains title compound (455mg).
MS (m/z): 520 [M-Cl]+
Elemental analysis value is (with C23H27F2N7O3S·HCl+2.5H2O meter)
Calculated value (%) C:45.96, H:5.53, N16.31
Measured value (%) C:46.19, H:5.34, N16.08
(1- { [6- { [(the 2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 97 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro carbethoxy hydrochloride
According to the method for 96 process 1,2 of embodiment, (2R) -3,3- dimethylbutane -2- amine is used to replace (1R) -1- ring Propylethylamine obtains title compound.
MS (m/z): 536 [M-Cl]+
Elemental analysis value is (with C24H31F2N7O3S·HCl+1.1H2O meter)
Calculated value (%) C:48.70, H:5.82, N16.56
Measured value (%) C:48.50, H:5.69, N16.49
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- of embodiment 98 Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester
According to the method for 96 process 1 of embodiment, (1R) -1- cyclopropylethyI amine is replaced using (1S) -1- cyclopropylethyI amine, Obtain title compound.
MS (m/z): 520 [M+H]+
(1- { [6- { [(the 2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 99 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester
According to the method for 96 process 1 of embodiment, (2S) -3,3- dimethylbutane -2- amine is used to replace (1R) -1- cyclopropyl Base ethamine, obtains title compound.
MS (m/z): 536 [M+H]+
Embodiment 100 (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) t-butyl carbamate
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 17 Carbonyl } piperidin-4-yl) t-butyl carbamate (200mg) n-butyl alcohol (1mL) solution in be added (2R) -3,3- dimethyl butyrate Alkane -2- amine (131mg), DIPEA (0.3mL) stir 4 hours at 80 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silicon Rubber column gel column chromatogram purification obtains title compound (183mg).
MS (m/z): 528 [M+H]+
(1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of embodiment 101 Base] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 24 Carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate (20mg) ethyl alcohol (0.5mL) solution in be added DIPEA (45 μ L), Tert-butylamine (23 μ L) stirs 4 hours at 130 DEG C in tube sealing.With silica gel chromatography reaction mixture, title is obtained Compound (2.4mg).
MS (m/z): 502 [M+H]+
Embodiment 102 (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- (dimethylamino) ethyl ester
According to the method for embodiment 40, piperidin-4-yl carbamic acid 2- (dimethylamino obtained in reference example 52 is used Base) ethyl ester replaces piperidin-4-yl urethanes, obtain title compound.
MS (m/z): 543 [M+H]+
(1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole-of embodiment 103 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 26 Carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester (15mg) DMF (1mL) solution in be added DIPEA (21 μ L), (1R) -1- cyclopropylethyI amine (10 μ L), is stirred 3 hours at 90 DEG C.With silica gel chromatography reaction mixture, title is obtained Compound (5mg).
MS (m/z): 538 [M+H]+
Embodiment 104 (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester
According to the method for embodiment 103, (2R) -3,3- dimethylbutane -2- amine is used to replace (1R) -1- cyclopropyl second Amine obtains title compound.
MS (m/z): 554 [M+H]+
Embodiment 105N- (1- { [6- (cyclopentyloxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 43, cyclopropyl-carbinol is replaced using cyclopentanol, obtains title compound.
MS (m/z): 481 [M+H]+
106 2- methoxyl group-N- of embodiment (1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide
According to the method for embodiment 92, (1R) -1- cyclopropylethyI amine is replaced using pentane -3- amine, obtains title compound Object.
MS (m/z): 486 [M+H]+
Embodiment 107N- (1- { [6- (2- ethyl-butoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
2- ethylbutane -1- is sequentially added into THF (1.0mL) suspension of 60% sodium hydride (4mg) under an argon (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in alcohol (29 μ L), reference example 15 Base] carbonyl } piperidin-4-yl) cyclopropane carboxamide (20mg), it is stirred at room temperature overnight.Water is added into reaction mixture, uses Ethyl acetate extraction, it is dry with anhydrous magnesium sulfate after washing organic layer with saturated sodium bicarbonate aqueous solution, it is concentrated under reduced pressure. It is residue obtained to use silica gel chromatography, obtain title compound (16mg).
MS (m/z): 496 [M+H]+
(1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-of embodiment 108 4- yl] carbonyl } piperidin-4-yl) methyl carbamate
Sequentially added under an argon into THF (1mL) suspension of 60% sodium hydride (4mg) pentane -3- alcohol (29 μ L), (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines-obtained in reference example 14 4- yl) methyl carbamate (20mg), it is stirred at room temperature 3 hours.Additional 60% sodium hydride (4mg), further at room temperature It is stirred overnight.Water is added into reaction mixture, is extracted with ethyl acetate.Organic layer is washed with saturated sodium bicarbonate aqueous solution Afterwards, dry with anhydrous magnesium sulfate, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (15mg)。
MS (m/z): 473 [M+H]+
(1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-of embodiment 109 4- yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using pentane -3- amine, is obtained Title compound.
MS (m/z): 472 [M+H]+
Embodiment 110N- [1- ({ 6- [(2- ethyl-butyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using 2- ethylbutane -1- amine, Obtain title compound.
MS (m/z): 496 [M+H]+
({ [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by embodiment 111N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 107,2- ethylbutane -1- alcohol is replaced using pentane -3- alcohol, obtains title compound Object.
MS (m/z): 483 [M+H]+
[1- ({ 6- [methyl (pentane -3- base) the amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 112 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methyl fourth is replaced using N- methylpentane -3- amine hydrochlorate Alkane -2- amine, obtains title compound.
MS (m/z): 486 [M+H]+
(1- { [6- { [(2R) -3,3- dimethylbutane -2- base] (methyl) amino } -2- (pyrazolo [5,1- of embodiment 113 B] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for embodiment 24, (2R)-N obtained in reference example 12,3,3- triptane -2- amine salt acid are used Salt replaces (2R) -3- methybutane -2- amine, obtains title compound.
MS (m/z): 500 [M+H]+
Embodiment 114N- (1- { [6- (2- ethyl-butoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) propionamide
Under an argon into THF (1.0mL) suspension of 60% sodium hydride (8.0mg) in ice-cold lower addition 2- ethyl fourth Alkane -1- alcohol (49mg) is stirred at room temperature 5 minutes.Then, N- (the 1- { [chloro- 2- (pyrazoles of 6- obtained in reference example 31 is added And [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) propionamide (40mg), it was stirred at room temperature Night.Water is added into reaction mixture, with ethyl acetate liquid separation.After washing organic layer with saturated sodium bicarbonate aqueous solution, with nothing Water magnesium sulfate is dry, is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (33mg).
MS (m/z): 485 [M+H]+
Embodiment 115N- (1- [6- { [(2R) -3,3- dimethylbutane -2- base] (methyl) amino } -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) propionamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 31 Base] carbonyl piperidin-4-yl) propionamide (20mg) n-butyl alcohol (1mL) solution in DIPEA (50 μ L) is added, in reference example 12 (the 2R)-N arrived, 3,3- triptane -2- amine hydrochlorates (14mg) stir 7 hours at 80 DEG C.Use silica gel chromatography Reaction mixture obtains title compound (9mg).
MS (m/z): 498 [M+H]+
Embodiment 116N- [1- ({ 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide
According to the method for embodiment 115, (2R)-N, 3,3- trimethyls are replaced using N- methylpentane -3- amine hydrochlorate Butane -2- amine hydrochlorate, obtains title compound.
MS (m/z): 484 [M+H]+
117 1- of embodiment ({ 6- [(4- hydroxy piperidine -1- base) carbonyl] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } amino) cyclopropanecarbonitrile hydrochloride
To [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- obtained in reference example 29 Hydroxy piperidine -1- base) ketone (20mg) ethyl alcohol (0.2mL) solution in be added DIPEA (12 μ L), 1- amino-cyclopropanecarbonitrile Hydrochloride (65mg) is reacted 1 hour at 130 DEG C with microwave reaction device.With silica gel chromatography reaction mixture, obtain Solids (16mg).It is molten that 4M hydrogen chloride-ethyl acetate is added into ethyl acetate (0.5mL) solution of obtained solid object (16mg) Liquid (16 μ L), evaporating solvent under reduced pressure.By residue powdered and leaching from ethyl acetate and hexane, it is dried, is marked It inscribes compound (12mg).
MS (m/z): 410 [M-Cl]+
[6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 118 Azoles -7- base) pyrimidine-4-yl] { 4- [(3- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone
To [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] { 4- obtained in reference example 32 [(3- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone (10mg) n-butyl alcohol (1mL) solution in be added DIPEA (15 μ L), (2R) -3,3- dimethylbutane -2- amine (7mg) stirs 5 hours at 80 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silicon Rubber column gel column chromatogram purification obtains title compound (11mg).
MS (m/z): 523 [M+H]+
Embodiment 119N- [1- ({ 6- [(2- methoxyl group -2- methyl-propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide
According to the method for embodiment 115, (2R)-N, 3,3- front threes are replaced using 2- methoxyl group -2- methylpropane -1- amine Base butane -2- amine hydrochlorate, obtains title compound.
MS (m/z): 486 [M+H]+
Embodiment 120 (4- hydroxy piperidine -1- base) { 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } methanone hvdrochloric acid salt
According to the method for embodiment 117,1- amino-cyclopropanecarbonitrile is replaced using N- methylpentane -3- amine hydrochlorate Hydrochloride obtains title compound.
MS (m/z): 429 [M-Cl]+
Embodiment 121N- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) propionamide
According to the method for embodiment 115, (2R)-N, 3,3- trimethyl fourths are replaced using (2R) -3- methybutane -2- amine Alkane -2- amine hydrochlorate, obtains title compound.
MS (m/z): 470 [M+H]+
Embodiment 122N- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane-is replaced using (2R) -3- methybutane -2- amine 2- amine, obtains title compound.
MS (m/z): 482 [M+H]+
Embodiment 123N- (1- { [6- { [(2S) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane-is replaced using (2S) -3- methybutane -2- amine 2- amine, obtains title compound.
MS (m/z): 482 [M+H]+
({ [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by embodiment 124N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using pentane -3- amine, is marked Inscribe compound.
MS (m/z): 482 [M+H]+
[1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 125 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate hydrochloride
According to the method for 24 process 1,2 of embodiment, (2R) -3- methybutane -2- is replaced using (2S)-butane -2- amine Amine obtains title compound.
MS (m/z): 458 [M-Cl]+
Elemental analysis value is (with C21H27N7O3SHCl meter)
Calculated value (%) C:51.06, H:5.71, N19.85
Measured value (%) C:51.00, H:5.73, N19.74
Specific rotatory power [α]D 25=2.2 (c=2.00, DMSO)
[1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 126 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using (2R)-butane -2- amine, Obtain title compound.
MS (m/z): 458 [M+H]+
[1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 127 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate hydrochloride
According to the method for 24 process 2 of embodiment, [1- ({ 6- [(2R)-butane -2- base ammonia obtained in embodiment 126 is used Base] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate carrys out generation For (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] carbonyl } piperidin-4-yl) methyl carbamate, obtain title compound.
MS (m/z): 458 [M-Cl]+
Elemental analysis value is (with C21H27N7O3S·HCl+0.7H2O meter)
Calculated value (%) C:49.79, H:5.85, N19.35
Measured value (%) C:49.73, H:5.75, N19.44
Specific rotatory power [α]D 25=-1.8 (c=2.00, DMSO)
Embodiment 128N- [1- ({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide
According to the method for embodiment 115, using 1- methyl cyclopropyl amine hydrochlorate (such as according to Chemische The method synthesis recorded in Berichte, 1986,119,3672-3693.) replace (2R)-N, 3,3- triptane -2- amine Hydrochloride obtains title compound.
MS (m/z): 454 [M+H]+
[6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 129 Azoles -7- base) pyrimidine-4-yl] { 4- [(5- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone
According to the method for embodiment 118, [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiophene obtained in reference example 34 is used Azoles -7- base) pyrimidine-4-yl] { 4- [(5- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone replaces the [chloro- 2- (pyrazolo of 6- [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] { 4- [(3- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone, it is marked Inscribe compound.
MS (m/z): 523 [M+H]+
130 2- methyl-N- of embodiment [1- (6- [(2- methybutane -2- base) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 16 Base] carbonyl piperidin-4-yl) -2- methyl propanamide (25mg) DMF (1mL) solution in be added DIPEA (50 μ L), 2- methyl fourth Alkane -2- amine (25mg) stirs 1 hour at 120 DEG C.Then, additional 2- methybutane -2- amine (25mg), is stirred at 120 DEG C 1 hour.Water is added into reaction solution, is extracted with ethyl acetate.After washing organic layer with saturated sodium bicarbonate aqueous solution, use is anhydrous Magnesium sulfate is dry, is concentrated under reduced pressure.With silica gel chromatography reaction mixture, title compound (12mg) is obtained.
MS (m/z): 484 [M+H]+
Embodiment 131N- [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide
According to the method for embodiment 115, (2R)-N, 3,3- triptane -2- are replaced using (2S)-butane -2- amine Amine hydrochlorate obtains title compound.
MS (m/z): 456 [M+H]+
[({ 6- [tert-butyl (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- for embodiment 132 Pyridine -4- base } carbonyl) piperidin-4-yl] methyl carbamate hydrochloride
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 14 Carbonyl } piperidin-4-yl) methyl carbamate (50mg) NMP (0.1mL) solution in be added DIPEA (103 μ L), N, 2- diformazan Base propane -2- amine (31mg) stirs 2 hours at 150 DEG C in tube sealing.With silica gel chromatography reaction mixture, obtain Solids (20mg).4M hydrogen chloride-ethyl acetate solution is added into ethyl acetate (2mL) solution of obtained solid object (20mg) (15μL).Reaction mixture is concentrated under reduced pressure, title compound (18mg) is obtained.
MS (m/z): 472 [M-Cl]+
{ 6- [tert-butyl (ethyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of embodiment 133 Base } (4- hydroxy piperidine -1- base) ketone
[process 1] (4- { [tert-butyl (dimethyl) silylation] oxygroup } piperidin-1-yl) { 6- [tert-butyl (ethyl) ammonia Base] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl ketone manufacture
To (4- { [tert-butyl (dimethyl) silylation] oxygroup } piperidin-1-yl) [the chloro- 2- of 6- obtained in reference example 30 (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone (150mg) ethyl alcohol (1mL) solution in DIPEA is added (706 μ L), tert-butylamine (333 μ L), is stirred 1 hour at 150 DEG C with microwave reaction device.Additional tert-butylamine (333 μ L), use is micro- Wave reaction unit futher stirs 1 hour at 150 DEG C.With silica gel chromatography reaction mixture, solids is obtained (111mg).Into DMF (0.6mL) solution of obtained solid object (30mg) in 60% sodium hydride of ice-cold lower addition (12mg), in room After lower stirring 15 minutes of temperature, it is added iodoethane (28 μ L), is stirred at room temperature overnight.Water is added into reaction solution, with acetic acid second Ester extraction.It is dry with anhydrous magnesium sulfate after saturated common salt water washing organic layer, it is concentrated under reduced pressure.It is residue obtained to use silica gel Column chromatography purifying, obtains title compound (28mg).
1H-NMR (CDCl3) δ: 0.06 (3H, s), 0.08 (3H, s), 0.90 (9H, s), 1.22-1.26 (4H, m), 1.57-1.63 (1H, m), 1.68 (9H, s), 1.82-1.90 (2H, m), 3.51-3.59 (1H, m), 3.63 (2H, q), 3.72-3.90 (3H, m), 4.01-4.09 (1H, m), 6.55 (1H, s), 6.97 (1H, s), 7.82 (1H, s), 8.41 (1H, s)
[process 2] { 6- [tert-butyl (ethyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } (4- hydroxy piperidine -1- base) ketone manufacture
To (4- { [tert-butyl (dimethyl) silylation] oxygroup } piperidin-1-yl) { 6- [tert-butyl (second obtained in process 1 Base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl ketone (28mg) THF (0.5mL) solution Middle addition 1M tetrabutyl ammonium fluoride (THF solution, 152 μ L), is stirred at room temperature overnight.Water is added into reaction solution, uses acetic acid Ethyl ester aqueous layer extracted.It is dry with anhydrous magnesium sulfate after saturated common salt water washing organic layer, it is concentrated under reduced pressure.It is residue obtained With silica gel chromatography, title compound (20mg) is obtained.
MS (m/z): 429 [M+H]+
(1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole-of embodiment 134 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid cyclopropyl ester
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 21 Carbonyl } piperidin-4-yl) carbamic acid cyclopropyl ester (25mg) DMF (1mL) solution in be added DIPEA (19 μ L), (1S) -1- ring Propylethylamine (7mg) stirs 1 hour at 100 DEG C.After reaction solution is diluted with ethyl acetate, saturated sodium bicarbonate water is added Solution carries out liquid separation, and water layer is further extracted with ethyl acetate, and combined organic layer is dry with anhydrous magnesium sulfate, is depressurized Concentration.It is residue obtained to use silica gel chromatography, obtain title compound (23mg).
MS (m/z): 496 [M+H]+
(1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of embodiment 135 Base] carbonyl } piperidin-4-yl) carbamic acid cyclopropyl ester
According to the method for embodiment 134, (1S) -1- cyclopropylethyI amine is replaced using tert-butylamine, obtains title compound.
MS (m/z): 484 [M+H]+
The fluoro- N- of 136 2,2- bis- of embodiment (1- [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 28 Base] carbonyl piperidin-4-yl) -2,2- two Fluorakil 100 (30mg) 2- propyl alcohol (2mL) solution in be added DIPEA (47 μ L), (2R) -3- methybutane -2- amine (18mg) stirs 3 hours at 80 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained to use silicon Rubber column gel column chromatogram purification obtains title compound (32mg).
MS (m/z): 492 [M+H]+
137 3- of embodiment [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] -1,1- dimethyl urea
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of 3- obtained in reference example 33 Base] carbonyl piperidin-4-yl) -1,1- dimethyl urea (20mg) DMF (1mL) solution in be added DIPEA (32 μ L), 2,2- diformazan Base propane -1- amine (12mg) stirs 4 hours at 60 DEG C.Reaction mixture is concentrated under reduced pressure, it is residue obtained to use silica gel column chromatography Purifying, obtains title compound (21mg).
MS (m/z): 485 [M+H]+
138 3- of embodiment (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -1,1- dimethyl urea
According to the method for embodiment 137,2,2- dimethylpropane -1- amine is replaced using (1R) -1- cyclopropylethyI amine, is obtained To title compound.
MS (m/z): 483 [M+H]+
[1- ({ 6- [(3- methy oxetane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 139 Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] carbamic acid propane -2- base ester
According to the method for embodiment 29, (2R) -3,3- diformazan is replaced using 3- methy oxetane -3- amine hydrochlorate Base butane -2- amine, obtains title compound.
MS (m/z): 500 [M+H]+
[1- ({ 6- [(bicyclic methyl propyl) the amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 140 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using Bicyclopropyl methylamine, is obtained To title compound.
MS (m/z): 496 [M+H]+
(the 1- { [6- phenoxy group -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } of embodiment 141 Piperidin-4-yl) methyl carbamate
Into THF (3mL) solution of phenol (34mg) in 60% sodium hydride of ice-cold lower addition (6mg), stir 5 minutes.It connects , (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl obtained in reference example 14 is added Base } piperidin-4-yl) methyl carbamate (30mg), it is stirred overnight at 70 DEG C.Water is added into reaction solution, uses ethyl acetate Extraction.It is dry with anhydrous magnesium sulfate after saturated common salt water washing organic layer, it is concentrated under reduced pressure.It is residue obtained to use silicagel column Chromatogram purification obtains title compound (19mg).
MS (m/z): 479 [M+H]+
142 4- of embodiment { [6- ({ 4- [(methoxycarbonyl) amino] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1- B] [1,3] thiazole -7- base) pyrimidine-4-yl] amino } piperidines -1- carboxylic acid tert-butyl ester
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] obtained in reference example 14 Carbonyl } piperidin-4-yl) methyl carbamate (100mg) 2- propyl alcohol (2.0mL) solution in be added DIPEA (144 μ L), 4- ammonia Phenylpiperidines -1- carboxylic acid tert-butyl ester (143mg) is reacted 1 hour at 150 DEG C with microwave reaction device.Use silica gel chromatography Reaction mixture obtains title compound (105mg).
MS (m/z): 585 [M+H]+
(1- { [6- (piperidin-4-yl amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-of embodiment 143 4- yl] carbonyl } piperidin-4-yl) methyl carbamate dihydrochloride
To { [6- ({ 4- [(methoxycarbonyl) amino] piperidin-1-yl } carbonyl) -2- (pyrrole of 4- obtained in embodiment 142 Azoles simultaneously [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] amino } 2M chlorination is added in piperidines -1- carboxylic acid tert-butyl ester (98mg) Hydrogen-methanol solution, is stirred at room temperature overnight.Reaction solution is concentrated under reduced pressure, simultaneously by gained residue with Ethyl acetate powdered Leaching is dried, and obtains title compound (91mg).
MS (m/z): 485 [M-2Cl-H]+
[1- ({ 6- [(1- anocy clopropyl) the amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 144 Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for embodiment 142,4- amino piperidine -1- carboxylic acid is replaced using 1- aminocyclopropane carbonitrile hydrochloride The tert-butyl ester obtains title compound.
MS (m/z): 467 [M+H]+
(1- { [6- { [(1S) -1- cyclopropylethyl] the amino } -5- methoxyl group -2- (pyrazolo [5,1-b] of embodiment 145 [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
Under an argon to (1- { [6- chloro-5-methoxyl -2- (pyrazolo [5,1-b] [1,3] obtained in reference example 35 Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate (15mg) 2- propyl alcohol (1mL) solution in be added TEA (19 μ L), (1S) -1- cyclopropylethyI amine (6mg), are stirred overnight at 100 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained With silica gel chromatography, title compound (16mg) is obtained.
MS (m/z): 500 [M+H]+
(1- { [6- { [(2R) -3,3- dimethylbutane -2- base] the amino } -5- methoxyl group -2- (pyrazolo of embodiment 146 [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for embodiment 145, (2R) -3,3- dimethylbutane -2- amine is used to replace (1S) -1- cyclopropyl second Amine obtains title compound.
MS (m/z): 516 [M+H]+
Embodiment 147 (3S) -3- { [6- ({ 4- [(methoxycarbonyl) amino] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] amino } pyrrolidines -1- carboxylic acid tert-butyl ester
According to the method for embodiment 142,4- amino piperazine is replaced using (S) -3- amino-pyrrolidine -1- carboxylic acid tert-butyl ester Pyridine -1- carboxylic acid tert-butyl ester, obtains title compound.
MS (m/z): 571 [M+H]+
Embodiment 148 (3R) -3- { [6- ({ 4- [(methoxycarbonyl) amino] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] amino } pyrrolidines -1- carboxylic acid tert-butyl ester
According to the method for embodiment 142,4- amino piperazine is replaced using (R) -3- amino-pyrrolidine -1- carboxylic acid tert-butyl ester Pyridine -1- carboxylic acid tert-butyl ester, obtains title compound.
MS (m/z): 571 [M+H]+
[1- ({ 2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [(the 3S)-pyrrolidin-3-yl ammonia of embodiment 149 Base] pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate dihydrochloride
According to the method for embodiment 143, { [6- ({ 4- [(methoxycarbonyl) ammonia of (3S) -3- as obtained in embodiment 147 Base] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] amino } pyrrolidines -1- carboxylic Tert-butyl acrylate obtains title compound.
MS (m/z): 471 [M-2Cl-H]+
[1- ({ 2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [(the 3R)-pyrrolidin-3-yl ammonia of embodiment 150 Base] pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate dihydrochloride
According to the method for embodiment 143, { [6- ({ 4- [(methoxycarbonyl) ammonia of (3R) -3- as obtained in embodiment 145 Base] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] amino } pyrrolidines -1- carboxylic Tert-butyl acrylate obtains title compound.
MS (m/z): 471 [M-2Cl-H]+
(1- { [6- { [(the 3R) -1- methylpyrrolidin- 3- yl] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 151 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
To [1- ({ 2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [(3R)-pyrroles obtained in embodiment 150 Alkane -3- base amino] pyrimidine-4-yl carbonyl) piperidin-4-yl] and methyl carbamate dihydrochloride (20mg) methanol (0.2mL) 2- picoline borane complex (40mg), 37% formalin (30 μ L), acetic acid (20 μ L) are added in solution, at room temperature It is stirred overnight.With silica gel chromatography reaction mixture, title compound (7mg) is obtained.
MS (m/z): 485 [M+H]+
Embodiment 152 (1- [6- { [(3R) -1- acetyl-pyrrolidine -3- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
To [1- ({ 2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [(3R)-pyrroles obtained in embodiment 150 Alkane -3- base amino] pyrimidine-4-yl carbonyl) piperidin-4-yl] and methyl carbamate dihydrochloride (20mg) THF (0.5mL) it is molten In ice-cold lower addition triethylamine (51 μ L), chloroacetic chloride (26 μ L) in liquid, it is stirred at room temperature 3 hours.Use silica gel chromatography Reaction mixture obtains title compound (8mg).
MS (m/z): 513 [M+H]+
[1- ({ 6- [(2S)-butane -2- base amino] -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 153 Azoles -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
According to the method for embodiment 145, (1S) -1- cyclopropylethyI amine is replaced using (2S)-butane -2- amine, is marked Inscribe compound.
MS (m/z): 488 [M+H]+
(1- { [6- { [(1S) -1- cyclopropylethyl] the amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] of embodiment 154 [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
Under an argon to (1- { [the chloro- 5- ethyoxyl -2- of 6- (pyrazolo [5,1-b] [1,3] obtained in reference example 36 Thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate (10mg) 2- propyl alcohol (1mL) solution in be added TEA (12 μ L), (1S) -1- cyclopropylethyI amine (4mg), are stirred overnight at 100 DEG C.Reaction solution is concentrated under reduced pressure, it is residue obtained With silica gel chromatography, title compound (5mg) is obtained.
MS (m/z): 514 [M+H]+
(1- { [6- { [(2R) -3,3- dimethylbutane -2- base] the amino } -5- ethyoxyl -2- (pyrazolo of embodiment 155 [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for embodiment 154, (2R) -3,3- dimethylbutane -2- amine is used to replace (1S) -1- cyclopropyl second Amine obtains title compound.
MS (m/z): 530 [M+H]+
(1- { [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- (pyridin-3-yl oxygroup) pyrimidine-of embodiment 156 4- yl] carbonyl } piperidin-4-yl) methyl carbamate
Into DMF (1.5mL) solution of pyridine -3- alcohol (34mg) in 60% sodium hydride of ice-cold lower addition (9.0mg), stirring 5 minutes.Then, (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-obtained in reference example 14 is added 4- yl] carbonyl } piperidin-4-yl) methyl carbamate (30mg), it is stirred at room temperature 30 minutes.It is anti-with silica gel chromatography Mixture is answered, title compound (23mg) is obtained.
MS (m/z): 480 [M+H]+
({ [6- (2- ethyl piperidine -1- base) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by embodiment 157N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide
To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 15 Base] carbonyl piperidin-4-yl) cyclopropane carboxamide (15mg) n-butyl alcohol (1mL) solution in be added DIEPA (151 μ L), 2- second Phenylpiperidines (79mg) are reacted 1 hour at 170 DEG C with microwave reaction device.With silica gel chromatography reaction mixture, obtain Title compound (18mg).
MS (m/z): 508 [M+H]+
(1-2- (pyrazolo [5,1-b] [1,3] thiazole -7- the base) -6- [(2,2,2- trifluoroethyl) amino] of embodiment 158 Pyrimidine -4- carbonyl piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methyl fourth is replaced using 2,2,2- trifluoroethylamine hydrochlorides Alkane -2- amine, obtains title compound.
MS (m/z): 484 [M+H]+
Embodiment 159N-1- [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [(thiophene -2- base) methyl] amino Pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using 2- thienylmethylamine, is obtained To title compound.
MS (m/z): 508 [M+H]+
Embodiment 160N-1- [6- [(furans -2- base) methyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using 2- furylmethylamine, is obtained To title compound.
MS (m/z): 492 [M+H]+
161 1- of embodiment [6- [(1R) -1- cyclohexyl-ethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- is replaced using (1R) -1- cyclohexylethylamine Amine obtains title compound.
MS (m/z): 512 [M+H]+
162 1- of embodiment [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [1- (pyridin-4-yl) ethyl] ammonia Yl pyrimidines -4- carbonyl] piperidin-4-yl methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- is replaced using 1- (4- pyridyl group) ethamine Amine obtains title compound.
MS (m/z): 507 [M+H]+
(1-6- [(2- cyclopropylethyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic for embodiment 163 Pyridine -4- carbonyl piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using 2- cyclopropylethyI amine, is obtained To title compound.
MS (m/z): 470 [M+H]+
164 3- of embodiment ([6-4- [(methoxycarbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] oxygroup methyl) azetidine -1- carboxylic acid tert-butyl ester
According to the method for embodiment 64,3,3- are replaced using 3- (hydroxymethyl) azetidine -1- carboxylic acid tert-butyl ester Dimethylbutane -2- alcohol, obtains title compound.
MS (m/z): 572 [M+H]+
Embodiment 165N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl cyclobutane carboxylic acid amides
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using cyclobutane phosgene, obtains title compound Object.
MS (m/z): 494 [M+H]+
Embodiment 166N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl pentamethylene carboxylic acid amides
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using Cyclopentanecarbonyl chloride, obtains title compound Object.
MS (m/z): 508 [M+H]+
Embodiment 167N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl cyclohexane carboxamide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using cyclohexanecarbonyl chloride, obtains title compound Object.
MS (m/z): 522 [M+H]+
Embodiment 168N- (1-6- [(trans- 4- hydroxy-cyclohexyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using trans- 4- aminocyclohexanol, Obtain title compound.
MS (m/z): 510 [M+H]+
Embodiment 169N-1- [6- [(1R) -1- cyclohexyl-ethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- is replaced using (1R) -1- cyclohexylethylamine Amine obtains title compound.
MS (m/z): 522 [M+H]+
Embodiment 170N-1- [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- [1- (pyridin-4-yl) ethyl] ammonia Yl pyrimidines -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- is replaced using 1- (4- pyridyl group) ethamine Amine obtains title compound.
MS (m/z): 517 [M+H]+
171 4- of embodiment [6-4- [(cyclopropane carbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] amino piperidine -1- carboxylic acid tert-butyl ester
According to the method for embodiment 16, (2R) -3,3- dimethyl butyrate is replaced using 4- amino piperidine -1- carboxylic acid tert-butyl ester Alkane -2- amine, obtains title compound.
MS (m/z): 595 [M+H]+
Embodiment 172N- (1-6- [( Alkane -4- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine -4- carbonyl piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using oxinane -4- amine, is obtained To title compound.
MS (m/z): 496 [M+H]+
Embodiment 173N- (1-6- [(oxetanes -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl piperidin-4-yl) cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane -2- amine is replaced using oxetanes -3- amine, Obtain title compound.
MS (m/z): 468 [M+H]+
(1-6- [(3- cyclopropyl -2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene of embodiment 174 Azoles -7- base) pyrimidine -4- carbonyl piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, replaced using 3- cyclopropyl -2,2- dimethylpropane -1- amine hydrochlorate (2R) -3- methybutane -2- amine, obtains title compound.
MS (m/z): 512 [M+H]+
175 1- of embodiment [6- ([1- (mesyl) piperidin-4-yl] methylamino) -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate
[process 1] 4- ([6-4- [(methoxycarbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] amino methyl) and piperidines -1- carboxylic acid tert-butyl ester manufacture
According to the method for 24 process 1 of embodiment, (2R)-is replaced using 4- (amino methyl) piperidines -1- carboxylic acid tert-butyl ester 3- methybutane -2- amine, obtains title compound.
MS (m/z): 599 [M+H]+
[process 2] 1- [6- ([1- (mesyl) piperidin-4-yl] methylamino) -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate manufacture
To ([6-4- [(methoxycarbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5,1-b] of 4- obtained in process 1 [1,3] thiazole -7- base) pyrimidine-4-yl] amino methyl) the middle addition 2M hydrogen chloride-methanol of piperidines -1- carboxylic acid tert-butyl ester (115mg) Solution (2mL) stirs 5 hours at 40 DEG C.Reaction solution is concentrated under reduced pressure, gained residue is washed into simultaneously leaching with ether, is carried out It is dry, obtain solids (105mg).Obtained solid object (25mg) is suspended in methylene chloride, DIPEA (38 μ L), methylsulphur is added Acyl chlorides (8mg), in ice-cold lower stirring 15 minutes.With silica gel chromatography reaction mixture, title compound (17mg) is obtained.
MS (m/z): 577 [M+H]+
Embodiment 176N-1- [6- [(1R)-bicyclic [2.2.1] heptane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 16, (2R) -3,3- dimethylbutane-is replaced using norbornane -2- amine hydrochlorate 2- amine, obtains title compound.
MS (m/z): 506 [M+H]+
(1-6- [(cis- 4- hydroxy-cyclohexyl) the amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 177 Pyrimidine -4- carbonyl piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- is replaced using cis- 4- aminocyclohexanol Amine obtains title compound.
MS (m/z): 500 [M+H]+
(1-6- [(trans- 4- hydroxy-cyclohexyl) the amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) of embodiment 178 Pyrimidine -4- carbonyl piperidin-4-yl) methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- is replaced using trans- 4- aminocyclohexanol Amine obtains title compound.
MS (m/z): 500 [M+H]+
179 1- of embodiment [6- (clopentylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl Base] piperidin-4-yl methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using cyclopentamine, obtains title Compound.
MS (m/z): 470 [M+H]+
180 1- of embodiment [6- (Cyclohexylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl Base] piperidin-4-yl methyl carbamate
According to the method for 24 process 1 of embodiment, (2R) -3- methybutane -2- amine is replaced using cyclohexylamine, obtains title Compound.
MS (m/z): 584 [M+H]+
(1-6- [(piperidin-4-yl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by embodiment 181N- Pyridine -4- carbonyl piperidin-4-yl) cyclopropane carboxamide dihydrochloride
To 4- obtained in embodiment 171 [6-4- [(cyclopropane carbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5, 1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] that 2M hydrogen chloride-methanol is added in amino piperidine -1- carboxylic acid tert-butyl ester (55mg) is molten Liquid (3mL) is stirred at room temperature 2 hours.Reaction solution is concentrated under reduced pressure, gained residue is washed into simultaneously leaching with ether, is done It is dry, obtain title compound (52mg).
MS (m/z): 495 [M-2Cl-H]+
Embodiment 182N-1- [6- [(2R) -3,3- dimethylbutane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl cyclohexane carboxamide
According to the method for embodiment 40, piperidin-4-yl is replaced using N- (piperidin-4-yl) cyclohexane carboxamide hydrochloride Urethanes obtains title compound.
MS (m/z): 538 [M+H]+
Embodiment 183N-1- [6- [(2R) -3,3- dimethylbutane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl benzamide
According to the method for embodiment 40, piperidin-4-yl urethane is replaced using N- (4- piperidyl) benzamide Ester obtains title compound.
MS (m/z): 532 [M+H]+
Embodiment 184N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl -2- methyl benzamide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using 2- methyl benzoyl chloride, obtains title compound Object.
MS (m/z): 530 [M+H]+
Embodiment 185N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl pyridine -2- carboxylic acid amides
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using pyridine -2- phosgene hydrochloride, is marked Inscribe compound.
MS (m/z): 517 [M+H]+
Embodiment 186N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl -2- methoxy benzamide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using 2- methoxy benzoyl chloride, is obtained titled Close object.
MS (m/z): 546 [M+H]+
Embodiment 187N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl pyridine -4- carboxylic acid amides
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using pyridine -4- phosgene hydrochloride, is marked Inscribe compound.
MS (m/z): 517 [M+H]+
Embodiment 188N- (1-6- [(1- Acetylpiperidin -4- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine -4- carbonyl piperidin-4-yl) cyclopropane carboxamide
Under an argon to (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- of N- obtained in reference example 15 Base) pyrimidine-4-yl] carbonyl piperidin-4-yl) cyclopropane carboxamide (30mg) 2- propyl alcohol (2mL) solution in be added DIPEA (48 μ L), 1- (4- amino -1- piperidyl) ethyl ketone (15mg), stirred 1 hour at 90 DEG C.Then, NMP (0.5mL) is added, 120 It is stirred 2 hours at DEG C.Reaction mixture is concentrated under reduced pressure, it is residue obtained to use silica gel chromatography, obtain title compound (30mg)。
MS (m/z): 537 [M+H]+
Embodiment 189N-1- [6- [1- (mesyl) piperidin-4-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
By (1-6- [(piperidin-4-yl) amino] -2- (pyrazolo [5,1-b] [1,3] thiophene of N- obtained in embodiment 181 Azoles -7- base) pyrimidine -4- carbonyl piperidin-4-yl) cyclopropane carboxamide dihydrochloride (20mg) is suspended in methylene chloride (2mL), adds Enter DIPEA (30 μ L), mesyl chloride (6mg), in ice-cold lower stirring 15 minutes.With silica gel chromatography reaction mixture, obtain To title compound (12mg).
MS (m/z): 573 [M+H]+
Embodiment 190N-1- [6- [(1S) -1- cyclopropylethyl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine -4- carbonyl] piperidin-4-yl pentanamide
According to the method for 30 process 3 of embodiment, chlorobenzoyl chloride is replaced using valeric chloride, obtains title compound.
MS (m/z): 496 [M+H]+
Embodiment 191N-1- [6- [(3R) -1- (Cyanoacetyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
Under an argon into THF (5mL) solution of N- [(3R)-pyrrolidin-3-yl] t-butyl carbamate (500mg) It is added 2- cyan-acetic ester (607mg) and 1,8- diazabicyclo [5.4.0] -7- hendecene (204mg) stirs at 40 DEG C 2 hours.After reaction solution is diluted with ethyl acetate, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, is extracted with ethyl acetate Water layer.After the anhydrous magnesium sulfate drying of combined organic layer, it is concentrated under reduced pressure.Solvent is evaporated off, it is residue obtained to use silicagel column Chromatogram purification obtains solids 1 (530mg).Obtained solid object 1 (530mg) is dissolved in 2M hydrogen chloride-methanol solution (8mL), It is stirred at room temperature overnight.Diethyl ether is added into reaction mixture, the solid that leaching is precipitated is dried, obtains solids 2 (331mg).To (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- of N- obtained in reference example 15 Base] carbonyl piperidin-4-yl) cyclopropane carboxamide (30mg) NMP (1mL) solution in be added DIEPA (48 μ L), above-mentioned solid Object 2 (26mg) stirs 3 hours at 120 DEG C.After reaction solution is diluted with ethyl acetate, saturated sodium bicarbonate aqueous solution is added It carries out liquid separation and water layer is extracted with ethyl acetate after saturated common salt water washing.Combined organic layer is dry with anhydrous magnesium sulfate Afterwards, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (22mg).
MS (m/z): 548 [M+H]+
192 4- of embodiment ([6-4- [(methoxycarbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] amino methyl) piperidines -1- carboxylate methyl ester
According to the method for 175 process 2 of embodiment, mesyl chloride is replaced using methylchloroformate, obtains title compound.
MS (m/z): 557 [M+H]+
Embodiment 193N-1- [6- [1- (propane -2- sulfonyl) piperidin-4-yl] amino -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 189, mesyl chloride is replaced using propane -2- sulfonic acid chloride, obtains title compound.
MS (m/z): 601 [M+H]+
194 4- of embodiment [6-4- [(cyclopropane carbonyl) amino] piperidines -1- carbonyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] amino piperidine -1- carboxylate methyl ester
According to the method for embodiment 189, mesyl chloride is replaced using methylchloroformate, obtains title compound.
MS (m/z): 553 [M+H]+
Embodiment 195N-1- [6- [(2R) -3,3- dimethylbutane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl heptamide
[process 1] (4- amino piperidine -1- base) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone manufacture
To (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo obtained in embodiment 100 [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl piperidin-4-yl) t-butyl carbamate (305mg) dichloromethane TFA (1mL) is added in alkane (1mL) solution, is stirred at room temperature 1 hour.After reaction solution is diluted with chloroform, unsaturated carbonate is added Hydrogen sodium water solution is neutralized, with chloroform aqueous layer extracted.After washing the organic layer merged with saturated sodium bicarbonate aqueous solution, with nothing Water magnesium sulfate is dry, is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (180mg).
MS (m/z): 428 [M+H]+
[process 2] N-1- [6- [(2R) -3,3- dimethylbutane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carbonyl] piperidin-4-yl heptamide manufacture
To (4- amino piperidine -1- base) obtained in process 1 [6- { [(2R) -3,3- dimethylbutane -2- base] amino } - 2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] ketone (10mg) methylene chloride (1mL) solution in ice Cold lower addition DIPEA (16 μ L), oenanthyl chloro (4mg), are stirred at room temperature 15 minutes.It is reacted and is mixed with silica gel chromatography Object obtains title compound (18mg).
MS (m/z): 540 [M+H]+
The chloro- N-1- of 196 2- of embodiment [6- [(2R) -3,3- dimethylbutane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl benzamide
According to the method for 195 process 2 of embodiment, oenanthyl chloro is replaced using 2- chlorobenzoyl chloride, obtains title compound.
MS (m/z): 566,568 [M+H]+
Embodiment 197N-1- [6- [(2R) -3,3- dimethylbutane -2- base] amino -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl -4- fluorobenzamide
According to the method for 195 process 2 of embodiment, oenanthyl chloro is replaced using 4- fluorobenzoyl chloride, obtains title compound.
MS (m/z): 550 [M+H]+
[1- ({ 6- [(1- propiono piperidin-4-yl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole-of embodiment 198 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate
To (1- { [6- (piperidin-4-yl amino) -2- (pyrazolo [5,1-b] [1,3] thiazole-obtained in embodiment 143 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate dihydrochloride (15mg) THF (0.5mL) solution in plus Enter TEA (38 μ L), propionyl chloride (17mg), is stirred at room temperature 2 hours.After reaction solution is diluted with ethyl acetate, saturation is added Sodium bicarbonate aqueous solution carries out liquid separation, and water layer is extracted with ethyl acetate.After the anhydrous magnesium sulfate drying of combined organic layer, into Row is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (9mg).
MS (m/z): 541 [M+H]+
(1- { [6- { [1- (Cyanoacetyl) piperidin-4-yl] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 199 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
To (1- { [6- (piperidin-4-yl amino) -2- (pyrazolo [5,1-b] [1,3] thiazole-obtained in embodiment 143 7- yl) pyrimidine-4-yl] carbonyl piperidin-4-yl) methyl carbamate dihydrochloride (15mg) THF (0.5mL) solution in plus Enter cyanoacetic acid (5mg), DIEPA (14 μ L), HATU (15mg), is stirred at room temperature overnight.Reaction solution ethyl acetate is dilute After releasing, saturated sodium bicarbonate aqueous solution is added and carries out liquid separation, water layer is extracted with ethyl acetate.By the anhydrous sulphur of combined organic layer After sour magnesium is dry, it is concentrated under reduced pressure.It is residue obtained to use silica gel chromatography, obtain title compound (3mg).
MS (m/z): 552 [M+H]+
(1- { [6- { [1- (methyl sulphonyl) piperidin-4-yl] amino } -2- (pyrazolo [5,1-b] [1,3] of embodiment 200 Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate
According to the method for embodiment 198, propionyl chloride is replaced using mesyl chloride, obtains title compound.
MS (m/z): 563 [M+H]+
201 1- of embodiment [6- [(3R) -1- (Cyanoacetyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate
According to the method for embodiment 191, ({ [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- for use Pyridine -4- base] carbonyl } piperidin-4-yl) methyl carbamate replaces N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide, obtain title compound.
MS (m/z): 538 [M+H]+
Embodiment 202N-1- [6- [(3R) -1- (Cyanoacetyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl propionamide
According to the method for embodiment 191, using N-, ({ [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) propionamide replaces N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide, obtain title compound.
MS (m/z): 536 [M+H]+
203 1- of embodiment [6- [(3R) -1- (Cyanoacetyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl urethanes
According to the method for embodiment 191, ({ [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- for use Pyridine -4- base] carbonyl } piperidin-4-yl) urethanes replaces N- (1- { [the chloro- 2- of 6- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide, obtain title compound.
MS (m/z): 552 [M+H]+
Embodiment 204N-1- [6- [(3S) -1- (Cyanoacetyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl cyclopropane carboxamide
According to the method for embodiment 191, N- is replaced using N- [(3S)-pyrrolidin-3-yl] t-butyl carbamate [(3R)-pyrrolidin-3-yl] t-butyl carbamate, obtains title compound.
MS (m/z): 548 [M+H]+
205 1- of embodiment [6- [(3R) -1- (cyclopropane carbonyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate
According to the method for embodiment 152, chloroacetic chloride is replaced using cyclopropanecarbonyl chloride, obtains title compound.
MS (m/z): 539 [M+H]+
206 1- of embodiment [6- [(3R) -1- (cyclobutanecarbonyl) pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate
According to the method for embodiment 152, chloroacetic chloride is replaced using cyclobutane phosgene, obtains title compound.
MS (m/z): 553 [M+H]+
207 1- of embodiment [6- [(3R) -1- bytyry pyrrolidin-3-yl] amino -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine -4- carbonyl] piperidin-4-yl methyl carbamate
According to the method for embodiment 152, chloroacetic chloride is replaced using butyl chloride, obtains title compound.
MS (m/z): 541 [M+H]+
Test example 1JAK tyrosine kinase inhibitory activity
1. the preparation of tested substance
Tested substance is deployed with dimethyl sulfoxide (DMSO) to 10mM, be further diluted to 1000 respectively with DMSO, 100,10, 1,0.1,0.01 μM of concentration.JAK1 is molten using 10mM, the DMSO of 1000 μM, 100 μM, 10 μM, 1 μM, 0.1 μM this 6 kinds of concentration Liquid, JAK2 and JAK3 use the DMSO solution of 1000 μM, 100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM this 6 kinds of concentration, with analysis Buffer dilutes 20 times, is configured to tested substance solution.As negative control, DMSO is diluted 20 times using with analysis buffer Obtained by solution.As analysis buffer, the Tween-20 of the Tris-HCl (pH7.5) of 15mM, 0.01 (v/v) % are used (Tween-20), the dithiothreitol (DTT) of 1mM.
The measurement of JAK tyrosine-kinase enzyme inhibition activity under 2.1mM ATP
Active measurement uses ELISA method.Tested substance solution is added to the amount (n=2) of every 10 μ L and is coated with strepto- 96 orifice plates (8 × 12 holes, Perkinelmer Inc. DELFIA stripe board (DELFIA Strip Plate) of Avidin (PerkinElmer society)), substrate solution (biotin labeling peptide substrates 1250nM (JAK1), 625nM are added with the amount of every 20 μ L The MgCl of the ATP (final concentration 1mM) of (JAK2, JAK3), 2.5mM, 25mM2, 15mM Tris-HCl (pH7.5), 0.01 (v/ V) dithiothreitol (DTT) of the Tween-20 of %, 1mM), it is stirred.Finally, with the amount addition JAK tyrosine kinase (card of every 20 μ L Receive Biological Science Co., Ltd (カ Le Na バ イ オ サ イ エ Application ス society)) (with analysis buffer be diluted to 7.5nM (JAK1), 0.75nM (JAK2, JAK3)), it is stirred, reaction in 1 hour is carried out at 30 DEG C.With the cleaning buffer solution (Tris- of 50mM The Tween-20 of HCl (pH7.5), the NaCl of 150mM, 0.02 (v/v) %) by after plate cleaning 4 times, envelope is added with the amount of every 150 μ L Close buffer (Tris-HCl (pH7.5), the 150mM of 0.1% bovine serum albumin (Bovine Serum Albumin), 50mM NaCl, 0.02 (v/v) % Tween-20), closing in 1 hour is carried out at 30 DEG C.Block buffer is removed, with every 100 μ L Amount addition horseradish peroxidase (Horse radish Peroxidase) mark antiphosphotyrosine antibody (BD biology section Company (BD Bioscience society)) (being diluted to 10000 times with Block buffer), it is incubated for 30 minutes at 30 DEG C.With clear Wash buffer cleans plate 4 times, and with the amount addition 3,3',5,5'-tetramethylbenzidine solution of every 100 μ L, (half well Tai Sike is public Take charge of (Na カ ラ イ テ ス Network society)), it develops the color 10 minutes.0.1M sulfuric acid is added with the amount of every 100 μ L, stops reaction.With enzyme mark Instrument (BIO-RAD company) measures the absorbance at 450nm.
3. the analysis of measurement result
For the absorbance measured, utilize SAS system (match company, bodyguard software study institute (SAS Institute Inc.)) Nonlinear regression analysis is carried out, is calculated the concentration (IC of the tested substance of each tyrosine kinase activity inhibition 50%50).Its result It is shown in table 1~6 below.
[table 1]
[table 2]
[table 3]
[table 4]
[table 5]
[table 6]
2 aspergillus of test example induces the inhibiting effect in air flue inflammatory model
By aspergillus fumigatus (Aspergillus fumigatus) extract (Greer Laboratories, Inc (Greer Laboratories society)) it is deployed with PBS solution to 400 μ g/mL.In the 0th day, the 1st day, the 7th day, the 8th day cigarette song by allotment Mould 50 μ L of solution is to mouse intranasal administration.It is carried out behind 1 hour of the tested substance administration of intranasal administration in the morning.Tested substance is given Medicine was carried out from the 0th day to the 9th day, was carried out daily 2 times sooner or later.Tested substance is set to be suspended in 0.5% methyl with the concentration of 10mg/mL Cellulose is administered orally with the dosage of 10mL/kg.In the 10th day recycling bronchus Alveolar lavage fluid (bronchoalveolar Lavage fluid:BALF), it is measured with Celltac (Japanese photoelectricity Co., Ltd. (Japanese photoelectricity society)) total white thin in BALF Born of the same parents' number.Then, it is calculated with ADVIA 120 (medical diagnosis company, Siemens (Siemens Healthcare Diagnostics society)) The ratio of eosinophil number in total leukocyte number out, multiplied by total leukocyte number, to calculate the acidophil granules in BALF Cell number.The eosinophil number of+0.5% methylcellulose administration group of aspergillus fumigatus extract-treated is set as inhibiting rate 0%, The eosinophil number of untreated+0.5% methylcellulose administration group of aspergillus fumigatus extract is set as inhibiting rate 100%, is calculated The inhibiting rate of each tested substance out is shown in table 7.
[table 7]
As shown in Table 7, each the compounds of this invention of embodiment has significant effect to internal inflammatory model.
Using the embodiment compound of above-mentioned table 7 as tested substance, test (test example 3 and test example 4) below is carried out.
The inhibiting effect of STAT6 phosphorylation caused by test example 3 is stimulated by IL-4
1. the preparation of tested substance
Tested substance is deployed with dimethyl sulfoxide (DMSO) to 10mM, is further diluted to 300,100 μM dense with DMSO Degree.100 times are diluted with RPMI1640 culture medium again, using the solution after dilution as tested substance solution.As negative control, make The solution obtained by DMSO is diluted 100 times with RPMI1640.
2. the active measurement of phosphorylation STAT6
By the DND39 cell liquid (cell number: 10 of the tested substance solution of 50 μ L or negative control solution and 400 μ L5It is a thin Born of the same parents) mixing, it is vibrated 30 minutes at 37 DEG C.The interleukin 4 (10ng/mL) of 50 μ L is added as excitor substance, oscillation 15 Minute.The fixating reagent Fixation buffer (BD Biological Science Co., Ltd) of 500 μ L is added, is vibrated 10 minutes, reaction is stopped Only.After being centrifuged off supernatant, the film permeabilization reagent Perm buffer III (BD Biological Science Co., Ltd) of 500 μ L is added, at 4 DEG C It is lower to be incubated for 30 minutes.After carrying out 2 cleaning operations with dye solution (Stain buffer) (BD Biological Science Co., Ltd), addition The anti-Stat6 of 647 mouse of Alexa Fluor (pY641) (BD Biological Science Co., Ltd) is incubated for 30 minutes in dark cold place.Gained is thin Cell lysis liquid is supplied to flow cytometer.The GEOMEAN value of interleukin 4 stimulation negative control group fluorescence intensity is set as inhibiting The GEOMEAN value of non-stimulated negative control group fluorescence intensity is set as inhibiting rate 100%, calculates the suppression of each tested substance by rate 0% As a result rate processed confirms that these tested substances inhibit the signal of IL-4.
The inhibiting effect of STAT5 phosphorylation caused by test example 4 is stimulated by IL-7
1. the preparation of tested substance
Tested substance is deployed with dimethyl sulfoxide (DMSO) to 10mM.100 times are diluted with RPMI1640 culture medium again, it will be dilute Solution after releasing is as tested substance solution.As negative control, using molten obtained by DMSO is diluted 100 times with RPMI1640 Liquid.
2. the active measurement of phosphorylation STAT5
The tested substance solution or negative control solution of 10 μ L are added into 100 μ L of people's fresh blood, vibrates 30 at 37 DEG C Minute.Using amount addition interleukin 7 (100ng/mL) of every 10 μ L as excitor substance, vibrate 15 minutes.Gu will crack/ Determine buffer (Lyse/fix buffer) (BD Biological Science Co., Ltd) and dilute 5 times with distilled water, adds 1.4mL.Then, it vibrates After ten minutes, it is centrifuged, cell is separated.After removing supernatant, the PBS of 1mL is added.After being centrifuged off PBS, 500 μ L are added Perm buffer III (BD Biological Science Co., Ltd), be incubated for 30 minutes at 4 DEG C.With dye solution Stain buffer After (BD Biological Science Co., Ltd) carries out 2 cleaning operations, the anti-Stat5 antibody (pY694) of 647 mouse of Alexa Fluor is added (BD Biological Science Co., Ltd) is incubated for 30 minutes in dark cold place.Gained cell solution is supplied to flow cytometer.IL-7 is stimulated into yin The GEOMEAN value of property control group fluorescence intensity is set as inhibiting rate 0%, by the GEOMEAN of non-stimulated negative control group fluorescence intensity Value is set as inhibiting rate 100%, calculates the inhibiting rate of each tested substance, as a result confirms that these tested substances inhibit the signal of IL-7.
As described in 1~test example of test example 4, the compounds of this invention shows JAK1 inhibitory activity, to internal inflammatory model Effectively.
A possibility that being utilized in industry
The compounds of this invention or its pharmaceutically acceptable salt show JAK1 inhibitory activity, therefore may be used as itself and exempt from Epidemic disease disease (such as rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, the graceful disease in Karst, generalized erythema wolf Sore, xerodermosteosis, multiple sclerosis, inflammatory bowel disease, behcet's disease, myasthenia gravis, type-1 diabetes mellitus, immune ball Albumen nephrosis, autoimmune thyroid disease, psoriasis, chorionitis, lupus nephritis, xerophthalmia, vasculitis (such as main artery Inflammation, giant cell arteritis, microscopic polyangitis, granulomatous Polyangiitis, eosinophilic granuloma's property Polyangiitis), skin Skin myositis, polymyositis, neuromyelitis optica etc.), diseases associated with inflammation (atopic dermatitis, contact dermatitis, eczema, pruritus, food It is object allergy, bronchial asthma, Eosinophilic's pneumonia, chronic obstructive pulmonary disease, allergic rhinitis, chronic nasosinusitis, thermophilic Eosinophil nasosinusitis, nasal polyp, allergic conjunctivitis, osteoarthritis, ankylosing spondylitis, Kawasaki disease, Buerger's disease, Nodular polyarteritis, IgA vasculitis etc.), proliferative diseases (such as solid carcinoma, blood cancer, lymphoid malignancies, bone Marrow proliferative diseases, Huppert's disease, pulmonary fibrosis, eosinophilia etc.), sudden deafness, diabetic nephropathy, The therapeutic agent of alopecia areata, bone marrow transplant rejection or organ transplantation rejection etc..
Preparation example 1
Tablet (piece for oral administration)
In 1 80mg of prescription
The mixed-powder tabletting of the ratio is shaped so that piece for oral administration is made with conventional method.

Claims (17)

1. the pyrazolo thiazolium compounds or its pharmaceutically acceptable salt that are indicated with the following general formula [1] or its hydrate,
[changing 1]
In formula,
R1Indicate hydrogen, the alkyl of C1~6 or the alkoxy of C1~6,
Z expression-OR3Or-NR4R5,
The R3Indicate the alkyl of C1~6, the alkyl of C1~6 replaced by the naphthenic base of C3~6, the naphthenic base of C3~6, phenyl or pyridyl group,
The R4Indicate hydrogen or the alkyl of C1~6,
The R5Indicate the alkyl of C1~6, the naphthenic base of C3~6, oxetanyl, THP trtrahydropyranyl, piperidyl or pyrrolidinyl,
R5Described in the alkyl of C1~6 can be selected from the group 1 of (1)~(5) or 2 groups replace:
(1) hydroxyl,
(2) alkoxy of C1~6 and the alkoxy of difluoro C1~6,
(3) naphthenic base of C3~6, by (alkoxy of difluoro C1~6) C1~6 naphthenic base of alkyl-substituted C3~6 and by the alcoxyl of C1~6 Base C1~6 naphthenic base of alkyl-substituted C3~6,
(4) can by (alkoxy of difluoro C1~6) the alkyl-substituted azetidinyl in C1~6 and THP trtrahydropyranyl and
(5) by fluorine-substituted phenyl and the phenyl replaced by the alkoxy of C1~6,
R5Described in the naphthenic base of C3~6 can be selected from the group 1 of (1)~(3) or 2 groups replace:
(1) hydroxyl,
(2) alkoxy of C1~6 and the alkoxy of difluoro C1~6 and
(3) itrile group,
R5Described in oxetanyl, THP trtrahydropyranyl, piperidyl or pyrrolidinyl can be selected from the group (1)~(3) Any 1 group replaces:
(1) alkyl of C1~6,
(2) alkyl-carbonyl of C1~6 and
(3) alkoxy carbonyl of C1~6,
R2Indicate hydroxyl or-NHR8,
The R8Indicate differentOxazolyl, pyridyl group, pyrimidine radicals, the pyridyl group being replaced by fluorine atoms, is taken by the alkyl of C1~6 thiazolyl Generation it is differentOxazolyl ,-COL1、-COOL2Or-SO2L3,
The L1It is any 1 group for being selected from the group (1)~(5):
(1) alkyl of C1~6, the alkyl of difluoro C1~6 and the alkyl of C1~6 replaced by the alkoxy of C1~6,
(2) naphthenic base of C3~6,
(3) phenyl,
(4) pyridyl group, thienyl and
(5) two alkyl aminos of C1~6 and the cycloalkyl amino of C3~6,
The L2It is any 1 group for being selected from the group (1)~(3):
(1) alkyl of C1~6, an alkyl of fluorine C1~6, the alkyl of difluoro C1~6, the alkyl of trifluoro C1~6 and replaced by the alkoxy of C1~6 The alkyl of C1~6,
(2) naphthenic base of C3~6 and
(3) two alkyl amino of C1~6 alkyl of C1~6,
The L3Indicate the alkyl of C1~6 or the naphthenic base of C3~6.
2. pyrazolo thiazolium compounds as described in claim 1 or its pharmaceutically acceptable salt or its hydrate, wherein R1 It is hydrogen.
3. pyrazolo thiazolium compounds as claimed in claim 2 or its pharmaceutically acceptable salt or its hydrate, wherein
Z is-NR4R5,
The R4It is hydrogen,
The R5It is the alkyl of C1~6 or the naphthenic base of C3~6,
R5Described in the alkyl of C1~6 can be selected from the group 1 group of (1)~(3) and replaced:
(1) hydroxyl,
(2) alkoxy of C1~6 and
(3) naphthenic base of C3~6,
R5Described in the naphthenic base of C3~6 can be selected from the group 1 group of (1)~(2) and replaced:
(1) hydroxyl and
(2) alkoxy of C1~6,
R2It is hydroxyl or-NHR8,
The R8It is differentOxazolyl, pyridyl group, pyrimidine radicals, the pyridyl group being replaced by fluorine atoms, is replaced by the alkyl of C1~6 thiazolyl It is differentOxazolyl ,-COL1Or-COOL2,
The L1It is any 1 group for being selected from the group (1)~(4):
(1) alkyl of C1~6, the alkyl of difluoro C1~6 and the alkyl of C1~6 replaced by the alkoxy of C1~6,
(2) naphthenic base of C3~6,
(3) phenyl and
(4) pyridyl group, thienyl,
The L2Be the alkyl of C1~6, an alkyl of fluorine C1~6, the alkyl of difluoro C1~6, the alkyl of trifluoro C1~6, by the alkoxy of C1~6 The alkyl of substituted C1~6 or the naphthenic base of C3~6.
4. pyrazolo thiazolium compounds as claimed in claim 3 or its pharmaceutically acceptable salt or its hydrate, wherein
R5It is the alkyl of C1~6, the alkyl of C1~6 that is optionally substituted by a hydroxyl group, the alkyl of C1~6 replaced by cyclopropyl or by the alkoxy of C1~6 The alkyl of substituted C1~6,
R2It is-NHR8。
5. pyrazolo thiazolium compounds as claimed in claim 3 or its pharmaceutically acceptable salt or its hydrate, wherein
R5It is the alkyl or the alkyl of C1~6 replaced by cyclopropyl that carbon number is 2~6,
R2It is-NHR8,
R8It is-COL1Or-COOL2,
The L1It is the alkyl or cyclopropyl that carbon number is 2~6,
The L2It is the alkyl of C1~6 or cyclopropyl.
6. pyrazolo thiazolium compounds as described in claim 1 or its pharmaceutically acceptable salt or its hydrate, wherein Pyrazolo thiazolium compounds is compound described in any one of following (1)~(135):
(1) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(2) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) acetamide,
(3) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(4) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(5) N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(6) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(7) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(8) N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclopropyl } methyl) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(9) N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclobutyl } methyl) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(10) N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclopenta } methyl) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(11) N- [1- ({ 6- [({ 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrans -4- base } methyl) amino] -2- (pyrazoles And [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(12) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(13) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(14) N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(15) N- [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(16) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(17) N- (1- { [6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(18) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) two Fluorakil 100 of -2,2-,
(19) N- (1- { [6- { [(1S, 2S) -2- methoxy cyclopentyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(20) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] (4- hydroxy piperidine -1- base) ketone,
(21) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) the fluoro- 2- methylpropane -2- base ester of carbamic acid 1-,
(22) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(23) [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine -4- base] (4- hydroxy piperidine -1- base) ketone,
(24) ({ [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) methyl carbamate,
(25) ({ [6- { [(2S) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) methyl carbamate,
(26) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) methyl carbamate,
(27) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) urethanes,
(28) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(29) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) benzamide,
(30) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) pyridine -3- carboxylic acid amides,
(31) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) thiophene -2- carboxylic acid amides,
(32) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(33) 1- cyclopropyl -3- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urea,
(34) [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine-4- base] [4- (pyrimidine -2 --amino) piperidin-1-yl] ketone,
(35) N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) cyclopropane carboxamide,
(36) N- [1- ({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(37) N- [1- ({ 6- [(1- methoxyl group -2- methylpropane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(38) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(39) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) urethanes,
(40) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(41) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) benzamide,
(42) N- (1- { [6- (cyclo propyl methoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(43) N- [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(44) N- (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) cyclopropane carboxamide,
(45) N- (1- { [6- (cyclopentyloxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) cyclopropane carboxamide,
(46) ({ [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(47) N- [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(48) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] [4- (1,2-Azoles -3- base amino) piperidin-1-yl] ketone,
(49) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone,
(50) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] { 4- [(3- methyl-1,2-Azoles -5- base) amino] piperidin-1-yl } ketone,
(51) N- (1- [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(52) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] (4- hydroxy piperidine - 1- yl) ketone,
(53) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) methyl carbamate,
(54) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid propane -2- base ester,
(55) [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(56) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine -4- base] (4- hydroxy piperidine -1- base) ketone,
(57) (1- { [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(58) [({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base } carbonyl) piperidin-4-yl] methyl carbamate,
(59) (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines - 4- yl) methyl carbamate,
(60) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) Methanesulfomide,
(61) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropyl-sulfonylamide,
(62) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) ethyl sulfonamide,
(63) N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) -2- methyl propanamide,
(64) N- (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) two Fluorakil 100 of -2,2-,
(65) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) urethanes,
(66) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyridine -2- Base amino) piperidin-1-yl] ketone,
(67) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) urethanes,
(68) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (1,3- thiophene Azoles -2- base amino) piperidin-1-yl] ketone,
(69) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyrimidine -2- Base amino) piperidin-1-yl] ketone,
(70) [1- ({ 6- [(2- methybutane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(71) (4- hydroxy piperidine -1- base) [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine -4- base] ketone,
(72) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid propyl ester,
(73) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(74) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(75) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(76) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid propyl ester,
(77) [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(78) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(79) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(80) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(81) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- methoxy acrylate,
(82) ({ [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) -2- methoxyl acetamide,
(83) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide,
(84) [1- ({ 6- [{ [1- (methoxy) cyclopropyl] methyl } (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(85) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(86) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(87) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(88) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(89) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) t-butyl carbamate,
(90) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid 2- methoxy acrylate,
(91) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- (dimethylamino) ethyl ester,
(92) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(93) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(94) ({ [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by 2- methoxyl group-N- Pyridine -4- base] carbonyl } piperidin-4-yl) acetamide,
(95) N- (1- { [6- (2- ethyl-butoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(96) (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) methyl carbamate,
(97) (1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) methyl carbamate,
(98) N- [1- ({ 6- [(2- ethyl-butyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(99) N- (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(100) [1- ({ 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(101) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(102) N- (1- { [6- (2- ethyl-butoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) propionamide,
(103) N- (1- [6- { [(2R) -3,3- dimethylbutane -2- base] (methyl) amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) propionamide,
(104) N- [1- ({ 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] propionamide,
(105) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] { 4- [(3- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone,
(106) N- [1- ({ 6- [(2- methoxyl group -2- methyl-propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide,
(107) (4- hydroxy piperidine -1- base) { 6- [methyl (pentane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl } ketone,
(108) N- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) propionamide,
(109) N- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(110) N- (1- { [6- { [(2S) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(111) N- (1- { [6- (pentane -3- base amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(112) [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(113) [1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(114) N- [1- ({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] propionamide,
(115) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl] { 4- [(5- fluorine pyridine -2- base) amino] piperidin-1-yl } ketone,
(116) 2- methyl-N- [1- ({ 6- [(2- methybutane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] propionamide,
(117) N- [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] propionamide,
(118) [1- ({ 6- [tert-butyl (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] methyl carbamate,
(119) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base] carbonyl } piperidin-4-yl) carbamic acid cyclopropyl ester,
(120) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid cyclopropyl ester,
(121) the fluoro- N- of 2,2- bis- (1- { [6- { [(2R) -3- methybutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) acetamide,
(122) 3- [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] -1,1- dimethyl urea,
(123) ({ [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by 3- Pyridine -4- base] carbonyl } piperidin-4-yl) -1,1- dimethyl urea,
(124) [1- ({ 6- [(3- methy oxetane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] carbamic acid propane -2- base ester,
(125) [1- ({ 6- [(bicyclic methyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(126) (1- { [6- phenoxy group -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines -4- Base) methyl carbamate,
(127) 4- { [6- ({ 4- [(methoxycarbonyl) amino] piperidin-1-yl } carbonyl) -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] amino } piperidines -1- carboxylic acid tert-butyl ester,
(128) (1- { [6- (piperidin-4-yl amino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) methyl carbamate,
(129) [1- ({ 6- [(1- anocy clopropyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] methyl carbamate,
(130) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(131) (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -5- methoxyl group -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(132) [1- ({ 6- [(2S)-butane -2- base amino] -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(133) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(134) (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(135) (1- { [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- (pyridin-3-yl oxygroup) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) methyl carbamate.
7. pyrazolo thiazolium compounds as described in claim 1 or its pharmaceutically acceptable salt or its hydrate, wherein Pyrazolo thiazolium compounds is compound described in any one of following (1)~(58):
(1) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(2) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(3) N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(4) N- (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(5) N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclopropyl } methyl) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(6) N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclobutyl } methyl) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(7) N- [1- (6- [({ 1- [(difluoro-methoxy) methyl] cyclopenta } methyl) amino] -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(8) N- [1- ({ 6- [({ 4- [(difluoro-methoxy) methyl] tetrahydro -2H- pyrans -4- base } methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(9) N- (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- methyl -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(10) N- (1- { [6- { [(1S, 2S) -2- (difluoro-methoxy) cyclopenta] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(11) N- [1- ({ 6- [(2,2- dimethyl propyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(12) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(13) N- (1- { [6- { [(2S) -1- (difluoro-methoxy) propane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiophene Azoles -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(14) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) methyl carbamate,
(15) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) urethanes,
(16) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) benzamide,
(17) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(18) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(19) N- (1- { [6- (cyclo propyl methoxy) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(20) N- [1- ({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(21) N- (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) cyclopropane carboxamide,
(22) N- [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl } carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(23) [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base] [4- (1,3- thiazol-2-yl amino) piperidin-1-yl] ketone,
(24) N- (1- [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(25) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) methyl carbamate,
(26) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid propane -2- base ester,
(27) [1- ({ 6- [(1- hydroxy-2-methyl propane -2- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(28) [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic Pyridine -4- base] (4- hydroxy piperidine -1- base) ketone,
(29) (1- { [6- { [(2S) -1- hydroxyl -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] Thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(30) [({ 6- [(3,3- dimethylbutane -2- base) oxygroup] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- Pyridine -4- base } carbonyl) piperidin-4-yl] methyl carbamate,
(31) (1- { [6- (cyclobutoxy group) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidines - 4- yl) methyl carbamate,
(32) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropyl-sulfonylamide,
(33) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) ethyl sulfonamide,
(34) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) urethanes,
(35) [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] [4- (pyridine -2- Base amino) piperidin-1-yl] ketone,
(36) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid propyl ester,
(37) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) -2- methoxyl acetamide,
(38) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(39) (1- { [6- { [(2S) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2- difluoro ethyl ester,
(40) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) t-butyl carbamate,
(41) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid 2- methoxy acrylate,
(42) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2- (dimethylamino) ethyl ester,
(43) (1- { [6- { [(1R) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(44) (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) carbamic acid 2,2,2- trifluoro ethyl ester,
(45) (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) methyl carbamate,
(46) N- [1- ({ 6- [(2- ethyl-butyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] cyclopropane carboxamide,
(47) N- (1- { [6- (pentane -3- base oxygroup) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl Base } piperidin-4-yl) cyclopropane carboxamide,
(48) [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] methyl carbamate,
(49) [1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] methyl carbamate,
(50) N- [1- ({ 6- [(1- methylcyclopropyl groups) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine -4- Base } carbonyl) piperidin-4-yl] propionamide,
(51) [1- ({ 6- [tert-butyl (methyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } carbonyl Base) piperidin-4-yl] methyl carbamate,
(52) (1- { [6- (tert-butylamino) -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperazine Pyridine -4- base) carbamic acid cyclopropyl ester,
(53) [1- ({ 6- [(3- methy oxetane -3- base) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] carbamic acid propane -2- base ester,
(54) [1- ({ 6- [(1- anocy clopropyl) amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] methyl carbamate,
(55) [1- ({ 6- [(2S)-butane -2- base amino] -5- methoxyl group -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) Pyrimidine-4-yl } carbonyl) piperidin-4-yl] methyl carbamate,
(56) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1,3] thiazole - 7- yl) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(57) (1- [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -5- ethyoxyl -2- (pyrazolo [5,1-b] [1, 3] thiazole -7- base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) methyl carbamate,
(58) (1- { [2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) -6- (pyridin-3-yl oxygroup) pyrimidine-4-yl] carbonyl } Piperidin-4-yl) methyl carbamate.
8. pyrazolo thiazolium compounds as described in claim 1 or its pharmaceutically acceptable salt or its hydrate, wherein Pyrazolo thiazolium compounds is compound described in any one of following (1)~(8):
(1) ({ [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) is phonetic by 1- by N- Pyridine -4- base] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(2) N- (1- { [6- { [(2R) -3,3- dimethylbutane -2- base] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(3) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) methyl carbamate,
(4) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) urethanes,
(5) N- (1- { [6- { [(1S) -1- cyclopropylethyl] (methyl) amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- Base) pyrimidine-4-yl] carbonyl } piperidin-4-yl) cyclopropane carboxamide,
(6) (1- { [6- { [(1S) -1- cyclopropylethyl] amino } -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine - 4- yl] carbonyl } piperidin-4-yl) carbamic acid propane -2- base ester,
(7) [1- ({ 6- [(2S)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] methyl carbamate,
(8) [1- ({ 6- [(2R)-butane -2- base amino] -2- (pyrazolo [5,1-b] [1,3] thiazole -7- base) pyrimidine-4-yl } Carbonyl) piperidin-4-yl] methyl carbamate.
9. medical composition, containing pyrazolo thiazolium compounds according to any one of claims 1 to 8 or its pharmaceutically may be used The salt of receiving or its hydrate are as effective component.
10.JAK1 inhibitor, containing pyrazolo thiazolium compounds according to any one of claims 1 to 8 or its pharmaceutically Acceptable salt or its hydrate are as effective component.
11. the therapeutic agent of diseases associated with inflammation, containing pyrazolo thiazolium compounds according to any one of claims 1 to 8 or Its pharmaceutically acceptable salt or its hydrate are as effective component.
12. therapeutic agent as claimed in claim 11, wherein diseases associated with inflammation be atopic dermatitis, eczema, bronchial asthma, It is Eosinophilic's pneumonia, chronic obstructive pulmonary disease, allergic rhinitis, Eosinophilic's nasosinusitis, nasal polyp, tetanic Property rachitis or Eosinophilic's esophagitis.
13. the therapeutic agent of autoimmune disease contains pyrazolo thiazole chemical combination according to any one of claims 1 to 8 Object or its pharmaceutically acceptable salt or its hydrate are as effective component.
14. therapeutic agent as claimed in claim 13, wherein autoimmune disease is rheumatoid arthritis, psoriasis pass Save inflammation, juvenile arthritis, the graceful disease in Karst, systemic lupus erythematosus, xerodermosteosis, inflammatory bowel disease, psoriasis, firmly Skin disease, xerophthalmia, aorto-arteritis, giant cell arteritis, microscopic polyangitis, granulomatous Polyangiitis, acidophilia meat The swollen property Polyangiitis of bud or neuromyelitis optica.
15. the therapeutic agent of proliferative diseases, containing pyrazolo thiazolium compounds according to any one of claims 1 to 8 or Its pharmaceutically acceptable salt or its hydrate are as effective component.
16. therapeutic agent as claimed in claim 15, wherein proliferative diseases are that solid carcinoma, blood cancer, lymphatic system are pernicious swollen Tumor, bone marrow proliferative diseases, Huppert's disease, pulmonary fibrosis or eosinophilia.
17. diabetic nephropathy, alopecia areata, bone marrow transplant rejection or the therapeutic agent of organ transplantation rejection, contain claim 1~8 Any one of described in pyrazolo thiazolium compounds or its pharmaceutically acceptable salt or its hydrate as effective component.
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